8-azaprostaglandin derivative compounds and drugs containing the compounds as the active ingredient

ABSTRACT

An 8-azaprostaglandin represented by formula (I) 
                         
(wherein all symbols have the same meanings as described in the specification), a pharmaceutically acceptable salt thereof or a cyclodextrin clathrate thereof. Since the compound represented by formula (I) binds to EP2 subtype among PGE receptor strongly, it is useful for preventive and/or treatment for immune diseases, allergic diseases, neuronal cell death, dysmenorrhea, premature birth, abortion, baldness, retinal neuropathy such as glaucoma, erectile dysfunction, arthritis, pulmonary injury, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, hepatic injury, acute hepatitis, liver cirrhosis, shock, nephritis, renal failure, circulatory diseases, systemic inflammatory response syndrome, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, still disease, Kawasaki Disease, burn, systemic granuloma, ulcerative colitis, Crohn disease, hypercytokinemia at dialysis, multiple organ failure, or bone diseases etc.

TECHNICAL FIELD

The present invention relates to 8-azaprostaglandins.

More specifically, the present invention relates to:

-   (1) an 8-azaprostaglandin derivative compound represented by formula    (I):

(wherein all symbols have the same meanings as described below), apharmaceutically acceptable salt thereof or a cyclodextrin clathratethereof,

-   (2) a process for the preparation thereof, and-   (3) a pharmaceutical composition comprising thereof as an active    ingredient.

BACKGROUND ART

Prostaglandin E₂ (abbreviated as PGE₂) has been known as a metabolite inthe arachidonate cascade. It has been known that PGE₂ possessescyto-protective activity, uterine contractive activity, a pain-inducingeffect, a promoting effect on digestive peristalsis, an awakeningeffect, a suppressive effect on gastric acid secretion, hypotensiveactivity and diuretic activity and so on.

A recent study has proved existence of various PGE subtype receptorspossessing a different physical role from each other. At present, fourreceptor subtypes are known and they are called EP₁, EP₂, EP₃, and EP₄(Negishi M., et al., J. Lipid Mediators Cell Signaling, 12, 379-391(1995)).

It is thought that EP₂ subtype receptor relates to inhibition ofproducing TNF-α and acceleration of producing IL-10. Therefore, thecompounds which can bind on EP₂ subtype receptor are expected to beuseful for the prevention and/or treatment of immune diseases (e.g.,autoimmune diseases such as amyotrophic lateral sclerosis (ALS),multiple sclerosis, Sjogren's syndrome, rheumatoid arthritis andsystemic lupus erythematosus etc., and rejection after organtransplantation), allergic diseases (e.g., asthma, allergic rhinitis,allergic conjunctivitis, atopic dermatitis, food allergy), neuronal celldeath, dysmenorrhea, premature birth, abortion, baldness, retinalneuropathy such as glaucoma, erectile dysfunction, arthritis, pulmonaryinjury, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronicobstructive pulmonary disease, hepatic injury, acute hepatitis, livercirrhosis, shock, nephritis (acute nephritis, chronic nephritis), renalfailure, circulatory diseases (e.g., hypertension, myocardial ischemia,chronic arterial obstruction, vibration disease), systemic inflammatoryresponse syndrome, sepsis, hemophagocytosis syndrome, macrophageactivation syndrome, still disease, Kawasaki Disease, burn, systemicgranuloma, ulcerative colitis, Crohn disease, hypercytokinemia atdialysis, multiple organ failure, and bone diseases (e.g., fracture,refracture, intractable fracture, nonunion, pseudarthrosis,osteomalacia, Paget's disease of bone, ankylosing spondylitis, bonemetastasis, osteroarthritis and destruction of bone/cartilage due tothese analogous diseases) etc. It is also considered that the compoundsare useful as an agent for accelerating the osteogenesis/cure after bonesurgery (e.g., fracture, bone graft, artificial arthrogenesis, spinalfusion, surgery for multiple myeloma, lung cancer, breast cancer, etc.,other bone repair) or substitute treatment for bone grafting. It isfurther considered that the compounds are useful agents for acceleratingthe regeneration of peridontium in periodontal disease etc.

As an 8-azaprostaglandin derivative, for example, compounds representedby formula (A):

(wherein Q^(A) is selected from the group consisting of —COOR^(3A),tetrazol-5-yl and —CONHR^(4A);

A^(A) is a single or cis double bond;

B^(A) is a single or trans double bond;

U^(A) is

R^(2A) is selected from the group consisting of α-thienyl, phenyl,phenoxy, monosubstituted phenyl and monosubstituted phenoxy, saidsubstituents being selected from the group consisting of chloro, fluoro,phenyl, methoxy, trifluoromethyl and alkyl having from one to threecarbon atoms;

R^(3A) is selected from the group consisting of hydrogen, alkyl havingfrom one to five carbon atoms, phenyl and p-biphenyl;

R^(4A) is selected from the group consisting of —COR^(5A) and—SO₂R^(5A); said R^(5A) being selected from the group consisting ofphenyl and alkyl having from one to five carbon atoms.), a C5 epimerthereof, or an alkali, alkaline earth or ammonium salt of the compoundhaving a carboxylate or tetrazol-5-yl group is described (ref. Japanesepublished unexamined application No. 53-21159 (U.S. Pat. No.4,177,346)).

Furthermore, in the specification, a compound represented by formula(A′):

(wherein, W^(A) is selected from the group consisting of —COOR^(3A),tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl (having from two to fivecarbon atoms in the acyloxy group), N-(phthalidyl)tetrazol-5-yl andN-(tetrahydropyran-2-yl)-tetrazol-5-y, and the other symbol have thesame meanings as described above.), a C5 epimer thereof, or an alkali,alkaline earth or ammonium salt of the compound having a carboxylate ortetrazol-5-yl group is described.

Moreover, a pyrrolidone represented by formula (B):

(wherein R^(1B) represents a straight or branched chain, saturated orunsaturated, aliphatic hydrocarbon radical having up to 10 carbon atoms,or a cycloaliphatic hydro-carbon radical having 3 to 7 carbon atoms,which radicals may be unsubstituted or substituted by one or more of thefollowing:

-   a) a straight or branched chain alkoxy-, alkylthio-, alkenyloxy- or    alkenylthio group of up to 5 carbon atoms,-   b) a phenoxy group which may carry one or two substituents selected    from optionally halogenated alkyl groups of 1 to 3 carbon atom(s),    halogen atoms, optionally halogenated phenoxy groups, and alkoxy    groups of 1 to 4 carbon atoms,-   c) a furyloxy, thienyloxy or benzyloxy group which may carry, on the    nucleus, one or two substituents selected from optionally    halogenated alkyl groups of 1 to 3 carbon atom(s), halogen atoms and    alkoxy groups of 1 to 4 carbon atoms,-   d) a trifluoromethyl or pentafluoroethyl group,-   e) a cycloalkyl group of 3 to 7 carbon atoms,-   f) a phenyl, thienyl or furyl group which may carry one or two    substituents selected from optionally halogenated alkyl groups of 1    to 3 carbon atom(s), halogen atoms, and alkoxy groups of 1 to 4    carbon atoms,

R^(2B) represents a straight or branched chain, saturated orunsaturated, aliphatic or cycloaliphatic hydrocarbon radical having upto 6 carbon atoms, or an araliphatic hydrocarbon radical having 7 or 8carbon atoms, and

-   -   n^(B) represents the integer two, three or four), corresponding        free acids thereof, or a physiologically tolerable metal or        amine salt thereof is described (ref. Japanese published        unexamined application No. 52-5764 (DT 2,528,664)).

In the other specification, a pyrrolidone of the same kind is described(ref. Japanese published unexamined application No. 52-73865 (BE849,346) and Japanese published unexamined application No. 52-133975 (BE854,268)).

Moreover, a compound represented by formula (c):

(wherein X^(1C) and X^(2C) are, independently, CH₂ or CO, X^(3C) is anitrogen atom or CH, R^(C) is a hydrogen atom or hydroxyl, R^(1C) andR^(2C) are, independently, CH₂ or CO, R^(3C) is CH₂, NH or oxygen atom,R^(4C) is NH, CH₂ or CO, R^(5C) is CH₂ or NH, R^(6C) is CH₂ or CO, m^(C)is between 0 and 4, n^(C) is between 0 and 5.) and a pharmaceuticallytolerable salt thereof is described (ref. EP 572,365).

Moreover, a compound represented by formula (D):

(when R^(1D) is a hydrogen atom or ethyl, R^(2D) is a hydrogen atom ormethyl, and R^(3D) is hydrogen. When R^(1D) is methyl, R^(2D) is ahydrogen atom and R^(3D) is methyl.) or a pharmaceutically tolerablesalt thereof is described. In the other specification, an8-azaprostanoic acid of the same kind is described (ref. Japanesepublished unexamined application No. 51-127068, Japanese publishedunexamined application No. 51-128961 and Japanese published unexaminedapplication No. 52-100467 (GB 1,523,178)).

Moreover, compounds represented by formulae (E), (E′) and (E″):

(wherein R^(E) is ester residue, dotted line is double bond or not, andwavy line is α-configuration or β-configuration.) are described (ref.Japanese published unexamined application No. 51-1461).

Moreover, a prostaglandin derivate represented by formula (F):

(wherein R^(1F) represents hydrogen, methyl or ethyl, R^(2F), R^(3F) andR^(4F), which are the same or different, each represents hydrogen ormethyl and R^(F) is selected from the groups consisting of:

(wherein R^(5F) represents hydrogen, methyl or ethyl, R^(6F) representsmethyl, ethyl or acetyl and R^(7F) and R^(8F) each represents hydrogenor a straight-chain alkyl group having from 1 to 3 carbon atom(s).).With the provisos that, when R^(7F) and R^(8F) represent hydrogen,R^(5F) is methyl or ethyl, or when R^(5F) represents methyl and R^(2F),R^(3F), R^(4F), R^(7F) and R^(8F) all represent hydrogen, R^(1F)represents ethyl.) is disclosed (ref. Japanese published unexaminedapplication No. 52-142060 (BE 852,941)). Furthermore, a prostaglandinderivative of the same kind is described (ref. Japanese publishedunexamined application No. 51-138671 (BE 839,761)).

Moreover, a racemic compound selected from the group represented byformulae (G) and (G′):

(wherein R^(G) is a hydrogen atom, lower alkyl group having from 1 to 4carbon atoms, when R^(G) is a hydrogen atom, the compounds may formpharmaceutically acceptable nontoxic salts; Z is trans-double bond orsaturated bond; waved line is α-configuration, β-configuration or amixture thereof.) is disclosed (ref. Japanese published unexaminedapplication No. 51-143663 (BE 841,165)).

DISCLOSURE OF THE INVENTION

The present inventors have studied to find out the compounds which canbind on EP₂ subtype receptor specifically, and which have strongagonistic activity. Finally, the compound of formula (I) was found outto meet this purpose, and this invention was accomplished. Furthermore,the present inventors also found out the compound which binds on bothEP₂ and EP₄ subtype receptor. The compound which binds on both EP₄ andEP₂ subtype receptor is expected additive or multiplier effect whentreatment of the disease associated with both subtype receptor.

The present invention relates to

-   (1) an 8-azaprostaglandin derivative compound represented by formula    (I):

wherein T is (1) an oxygen atom or (2) a sulfur atom;

X is (1) —CH₂—, (2) —O— or (3) —S—;

A is A¹ or A²;

A¹ is (1) C2-8 straight-chain alkylene optionally substituted by 1 to 2C1-4 alkyl(s), (2) C2-8 straight-chain alkenylene optionally substitutedby 1 to 2 C1-4 alkyl(s) or (3) C2-8 straight-chain alkynylene optionallysubstituted by 1 to 2 C1-4 alkyl(s);

A² is -G¹-G²-G³-;

G¹ is (1) C1-4 straight-chain alkylene optionally substituted by 1 to 2C1-4 alkyl(s), (2) C2-4 straight-chain alkenylene optionally substitutedby 1 to 2 C1-4 alkyl(s) or (3) C2-4 straight-chain alkynylene optionallysubstituted by 1 to 2 C1-4 alkyl(s);

G² is (1) —Y—, (2)-ring1-, (3) —Y-ring1-, (4)-ring1-Y— or (5) —Y—C1-4alkylene-ring1-;

Y is (1) —S—, (2) —SO—, (3) —SO₂—, (4) —O— or (5) —NR¹—;

R¹ is (1) a hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl;

G³ is (1) a bond, (2) C1-4 straight-chain alkylene optionallysubstituted by 1 to 2 C1-4 alkyl(s), (3) C2-4 straight-chain alkenyleneoptionally substituted by 1 to 2 C1-4 alkyl(s) or (4) C2-4straight-chain alkynylene optionally substituted by 1 to 2 C1-4alkyl(s);

D is D¹ or D²;

D¹ is (1) —COOH, (2) —COOR², (3) tetrazol-5-yl or (4) —CONR³SO₂R⁴;

R² is (1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenylor (4) biphenyl;

R³ is (1) a hydrogen atom or (2) C1-10 alkyl;

R⁴ is (1) C1-10 alkyl or (2) phenyl;

D² is (1) —CH₂OH, (2) —CH₂OR⁵, (3) hydroxy, (4) —OR⁵, (5) formyl, (6)—CONR⁶R⁷, (7) —CONR⁶SO₂R⁸, (8) —CO—(NH-amino acid residue-CO)_(m)—OH,(9) —O—(CO-amino acid residue-NH)_(m)—H, (10) —COOR⁹, (11)—OCO—R^(10, ()12) —COO-Z¹-Z²-Z³, or

R⁵ is C1-10 alkyl;

R⁶ and R⁷ are, each independently, (1) a hydrogen atom or (2) C1-10alkyl;

R⁸ is C1-10 alkyl substituted by phenyl;

R⁹ is (1) C1-10 alkyl substituted by biphenyl optionally substituted by1 to 3 substituent(s) selected from C1-10 alkyl, C1-10 alkoxy andhalogen or (2) biphenyl substituted by 1 to 3 substituent(s) selectedfrom C1-10 alkyl, C1-10 alkoxy and halogen atom;

R¹⁰ is (1) phenyl or (2) C1-10 alkyl;

m is 1 or 2;

Z¹ is (1) C1-15 alkylene, (2) C2-15 alkenylene or (3) C2-15 alkynylene;

Z² is (1) —CO—, (2) —OCO—, (3) —COO—, (4) —CONR^(Z1)—, (5) —NR^(Z2)CO—,(6) —O—, (7) —S—, (8) —SO₂—, (9) —SO₂—NR^(Z2)—, (10) —NR^(Z2)SO₂—, (11)—NR^(Z3)—, (12) —NR^(Z4)CONR^(Z5)—, (13) —NR^(Z6)COO—, (14) —OCONR^(Z7)—or (15) —OCOO—;

Z³ is (1) a hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl, (4) C2-15alkynyl, (5) ringZ or (6) C1-10 alkyl substituted by C1-10 alkoxy, C1-10alkylthio, C1-10 alkyl-NR^(Z8)— or ringZ;

ringZ is (1) C3-15 mono-, bi- or tri-carbocyclic aryl which may bepartially or fully saturated or (2) 3- to 15-membered mono-, bi- ortri-heterocyclic aryl which may be partially or fully saturated andcontains 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfuratom(s);

R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8) are,each independently, a hydrogen atom or C1-15 alkyl;

R^(Z1) and Z³ may be taken together with the nitrogen atom to which theyare attached to form a 5- to 7-membered saturated mono-heterocyclicring, and the heterocyclic ring may contain other one hetero atomselected from oxygen, nitrogen and sulfur atoms;

ringZ and the saturated mono-heterocyclic ring formed by R^(Z1), Z³ andthe nitrogen atom to which they are attached may be substituted by 1-3groups selected from following (1) to (4):

(1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15 alkynyl, (4) C1-10 alkylsubstituted by C1-10 alkoxy, C1-10 alkylthio or C1-10 alkyl-NR^(Z9)—;

R^(Z9) is a hydrogen atom or C1-10 alkyl;

E is E¹ or E²;

E¹ is

R¹¹ is (1) C1-10 alkyl, (2) C1-10 alkylthio, (3) C1-10 alkyl substitutedby C3-8 cycloalkyl, (4) C1-10 alkyl substituted by ring2 or (5) C1-10alkyl substituted by —W¹— W²-ring2;

W¹ is (1) —O—, (2) —S—, (3) —SO—, (4) —SO₂—, (5) —NR¹¹⁻¹—, (6) carbonyl,(7)-NR¹¹⁻¹SO₂—, (8) carbonylamino or (9) aminocarbonyl;

R¹⁻¹¹ is (1) a hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl;

W² is (1) a bond or (2) C1-8 alkyl optionally substituted by C1-4 alkyl,halogen or hydroxy;

E² is (1) U¹—U²—U³ or (2) ring4;

U¹ is (1) C1-4 alkylene, (2) C2-4 alkenylene, (3) C2-4 alkynylene,(4)-ring3-, (5) C1-4 alkylene-ring3-, (6) C2-4 alkenylene-ring3- or (7)C2-4 alkynylene-ring3-;

U² is (1) a bond, (2) —CH₂—, (3) —CHOH—, (4) —O—, (5) —S—, (6) —SO—, (7)—SO₂—, (8) —NR¹²—, (9) carbonyl, (10) —NR¹²SO₂—, (11) carbonylamino or(12) aminocarbonyl;

R¹² is (1) a hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl;

U³ is (1) C1-8 alkyl optionally substituted by 1 to 3 substituent(s)selected from C1-10 alkyl, halogen, hydroxy, alkoxy, alkylthio andNR¹³R¹⁴, (2) C2-8 alkenyl optionally substituted by 1 to 3substituent(s) selected from C1-10 alkyl, halogen, hydroxyl, alkoxy,alkylthio and —NR¹³R¹⁴, (3) C2-8 alkynyl optionally substituted by 1 to3 substituent(s) selected from C1-10 alkyl, halogen, hydroxy, alkoxy,alkylthio and —NR¹³R¹⁴, (4) C1-8 alkyl substituted by ring4 or (5)ring4;

R¹³ and R¹⁴ are, each independently, (1) a hydrogen atom or (2) C1-10alkyl;

ring1, ring2, ring3 or ring4 may be substituted by 1 to 5 R;

R is (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10alkoxy, (5) C1-10 alkylthio, (6) halogen, (7) hydroxy, (8) nitro, (9)—NR¹⁵R¹⁶, (10) C1-10 alkyl substituted by C1-10 alkoxy, (11) C1-10 alkylsubstituted by 1 to 3 halogen atom(s), (12) C1-10 alkyl substituted byC1-10 alkoxy substituted by 1 to 3 halogen atom(s), (13) C1-10 alkylsubstituted by —NR¹⁵R¹⁶, (14) ring5, (15) —O-ring5, (16) C1-10 alkylsubstituted by ring5, (17) C2-10 alkenyl substituted by ring5, (18)C2-10 alkynyl substituted by ring5, (19) C1-10 alkoxy substituted byring5, (20) C1-10 alkyl substituted by —O-ring5, (21) COOR¹⁷, (22) C1-10alkoxy substituted by 1 to 4 halogen atom(s), (23) formyl, (24) C1-10alkyl substituted by hydroxy or (25) C2-10 acyl;

R¹⁵, R¹⁶ and R¹⁷ are, each independently, (1) a hydrogen atom or (2)C1-10 alkyl;

ring5 may be substituted by 1 to 3 substituent(s) selected fromfollowing (1)-(9):

(1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10 alkoxy,(5) C1-10 alkyl substituted by C1-10 alkoxy, (6) halogen atom, (7)hydroxy, (8) C1-10 alkyl substituted by 1 to 3 halogen atom(s), (9)C1-10 alkyl substituted by C1-10 alkoxy substituted by 1 to 3 halogenatom(s);

ring1, ring2, ring3, ring4 and ring5 are, each independently,

(1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially orfully saturated or (2) 3- to 15-membered mono-, bi- or tri-heterocyclicaryl which may be partially or fully saturated and contains a heteroatom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygen and/or 1 to 2sulfur atom(s); and

wherein

-   1) when E is E², E² is U¹—U²—U³, and U¹ is C2 alkylene or C2    alkenylene, U² is not —CHOH—,-   2) when U³ is C1-8 alkyl substituted by at least one hydroxy, U¹—U²    is not C2 alkylene or C2 alkenylene,-   3) when A is A¹ and D is D¹, then E is not E¹,-   4) when T is oxygen atom, X is —CH₂—, D is D¹, D¹ is COOH, A is A¹,    A¹ is C2-8 straight-chain alkylene, E is E², E² is U¹—U²—U³, U¹ is    C1-4 alkylene and U³ is C1-8 alkyl, then U² is not a bond, —CH₂—,    —NR¹²— or carbonyl,-   5) when T is an oxygen atom, X is —CH₂—, D is D¹, D¹ is COOH, A is    A², G¹ is C1-4 alkylene, G² is —O— or —NR¹—, G³ is a bond or C1-4    alkylene, E is E², E² is U¹—U²—U³, U¹ is C1-4 alkylene and U³ is    C1-8 alkyl, the U² is not a bond, —CH₂—, —NR¹²— or carbonyl,-   6) when T is an oxygen atom, X is —CH₂—, D is D¹, E is E², E² is    U¹—U²—U³, U¹ is C2 alkylene or C2 alkenylene and U² is —CO—, then A    is not A¹,-   7)    4-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-oct-1-enyl]-5-oxo-pyrrolidin-1-yl}ethyl)thio]butanoic    acid and    4-{2-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-ethyl}-benzoic    acid are excluded,

a pharmaceutically acceptable salt thereof or a cyclodextrin clathratethereof,

-   (2) a process for the preparation thereof, and-   (3) a pharmaceutical composition comprising thereof as an active    ingredient.

In the present invention, C1-4 alkyl includes methyl, ethyl, propyl,butyl and isomers thereof.

In the present invention, C1-8 alkyl includes methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.

In the present invention, C1-10 alkyl includes methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof.

In the present invention, C1-15 alkyl includes methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,tridecyl, tetradecyl, pentadecyl and isomers thereof.

In the present invention, C2-8 alkenyl includes ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl and isomers thereof.

In the present invention, C2-10 alkenyl includes ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl andisomers thereof.

In the present invention, C2-15 alkenyl includes ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and isomersthereof.

In the present invention, C2-8 alkynyl includes ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl and isomers thereof.

In the present invention, C2-10 alkynyl includes ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl andisomers thereof.

In the present invention, C2-15 alkynyl includes ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl,undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl and isomersthereof.

In the present invention, C1-4 straight-chain alkylene includesmethylene, ethylene, trimethylene and tetramethylene.

In the present invention, C2-8 straight-chain alkylene includesethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene and octamethylene.

In the present invention, C1-4 alkylene includes methylene, ethylene,trimethylene, tetramethylene and isomers thereof.

In the present invention, C1-15 alkylene includes methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene, nonamethylene, decamethylene,undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene,pentadecamethylene and isomers thereof.

In the present invention, C2-4 straight-chain alkenylene includesethenylene, propenylene, butenylene and isomers thereof.

In the present invention, C2-8 straight-chain alkenylene means C2-8alkenylene which has 1 to 2 double bond(s). It includes ethenylene,propenylene, butenylene, butadienylene, pentenylene, pentadienylene,hexenylene, hexadienylene, heptenylene, heptadienylene, octenylene andoctadienylene.

In the present invention, C2-4 alkenylene includes ethenylene,propenylene, butenylene and isomers thereof.

In the present invention, C2-15 alkenylene includes ethenylene,propenylene, butenylene, pentenylene, hexenylene, heptenylene,octenylene, nonenylene, decenylene, undecenylene, dodecenylene,tridecenylene, tetradecenylene, pentadecenylene and isomers thereof.

In the present invention, C2-4 straight-chain alkynylene includesethynylene, propynylene and butynylene.

In the present invention, C2-8 straight-chain alkynylene means C2-8alkenylene which has 1 to 2 triple bond(s). It includes ethynylene,propynylene, butynylene, butadiynylene, pentynylene, pentadiynylene,hexynylene, hexadiynylene, heptynylene, heptadiynylene, octynylene andoctadiynylene.

In the present invention, C2-4 alkynylene includes ethynylene,propynylene, butynylene and isomers thereof.

In the present invention, C2-15 alkynylene includes ethynylene,propynylene, butynylene, pentynylene, hexynylene, heptynylene,octynylene, nonynylene, decynylene, undecynylene, dodecynylene,tridecynylene, tetradecynylene, pentadecynylene and isomers thereof.

In the present invention, C1-10 alkoxy includes methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy,decyloxy and isomers thereof.

In the present invention, C1-10 alkylthio includes methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio,octylthio, nonylthio, decylthio and isomers thereof.

In the present invention, C3-8 cycloalkyl includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the present invention, C2-10 acyl includes ethanoyl, propanoyl,butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyland isomers thereof.

In the present invention, biphenyl includes 2-phenylphenyl,3-phenylphenyl or 4-phenylphenyl.

In the present invention, halogen atom includes fluoride, chloride,bromide and iodide atom.

In the present invention, amino acid residue in —CO—(NH-amino acidresidue-CO)_(m)—OH and —O—(CO-amino acid residue-NH)_(m)—H includes theamino acid residue of natural amino acid or abnormal amino acid. Naturalamino acids or abnormal amino acid include, for example, glycine,alanine, valine, leucine, isoleucine, serine, threonine, cystein,methionine, proline, asparagine, glutamine, phenylalanine, tyrosine,tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidine,p-alanine, cystathionine, cystine, homoserine, isoleucine, lanthionine,norleucine, norvaline, ornithine, sarcosine, thyronine etc.

In amino acid residue in —CO—(NH— amino acid residue-CO)_(m)—OH and—O—(CO-amino acid residue-NH)_(m)—H, an amino acid with protecting groupis included.

In the present invention, C3-15 mono-, bi- or tri-carbocyclic aryl whichmay be partially or fully saturated represented by ring1, ring2, ring3,ring4, ring5 or ringZ includes, for example, cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cycloundecane, cyclododecane, cyclotridecane,cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene,cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,heptalene, perhydroheptalene, biphenylene, as-indacene, s-indacene,acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene,anthracene, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane,bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene,adamantane, noradamantane etc.

In the present invention, among the 3- to 15-membered mono-, bi- ortri-heterocyclic aryl which may be partially or fully saturated andcontains a hetero atom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygen,and/or 1 to 2 sulfur atom(s) represented by ring1, ring2, ring3, ring4,ring5 or ringZ, 3- to 15-membered mono-, bi- or tri-heterocyclic arylcontaining a hetero atom(s) selected from 1 to 4 nitrogen, 1 to 2oxygen, and/or 1 to 2 sulfur atom(s) includes, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, beta-carboline, acridine, phenazine,dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine,phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidinering etc.

The 3- to 15-membered mono-, bi- or tri-heterocyclic aryl which ispartially or fully saturated and contains a hetero atom(s) selected from1 to 4 nitrogen, 1 to 2 oxygen and/or 1 to 2 sulfur atom(s) includesaziridine, azetidine, azocane, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole(oxazolidine),dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole,tetrahydrothiazole(thiazolidine), dihydroisothiazole,tetrahydroisothiazole(isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, oxathiane, indoline, isoindoline,dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran,perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene,dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine,benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine,dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane,dioxaindan, benzodioxane, chroman, benzodithiolane, benzodithiane ringetc.

In the present invention, C3-10 mono- or bi-carbocyclic aryl which maybe partially or fully saturated includes, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene,cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene,cyclooctadiene, benzene, pentalene, perhydropentalene, azulene,perhydroazulene, indene, perhydroindene, indane, naphthalene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,spiro[4.4]nonane, spiro[4.5]decane, bicyclo[2.2.1]heptane,bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene,adamantane, noradamantane etc.

In the present invention, among the 3- to 10-membered mono- orbi-heterocyclic aryl which may be partially or fully saturated andcontains a hetero atom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygen,and/or 1 to 2 sulfur atom(s), 3- to 10-membered mono- or bi-heterocyclicaryl containing a hetero atom(s) selected from 1 to 4 nitrogen, 1 to 2oxygen, and/or 1 to 2 sulfur atom(s) includes, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole,benzotriazole ring etc.

The 3- to 10-membered mono- or bi-heterocyclic aryl which is partiallyor fully saturated and contains a hetero atom(s) selected from 1 to 4nitrogen, 1 to 2 oxygen and/or 1 to 2 sulfur atom(s) includes aziridine,azetidine, azocane, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydroazepine,tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole(oxazolidine),dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole,tetrahydrothiazole(thiazolidine), dihydroisothiazole,tetrahydroisothiazole(isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, oxathiane, indoline, isoindoline,dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran,perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene,dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, dihydroisothiazole,tetrahydroisothiazole(isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane,dithiane ring etc.

In the present invention, C5 or 6 mono-carbocyclic aryl which may bepartially or fully saturated includes, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene,cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene,cycloheptadiene, benzene etc.

In the present invention, among the 5- or 6-membered mono-heterocyclicaryl which may be partially or fully saturated and contains a heteroatom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygen, and/or 1 to 2sulfur atom(s), 5- or 6-membered mono-heterocyclic aryl containing ahetero atom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygen, and/or 1 to2 sulfur atom(s) includes, for example, pyrrole, imidazole, triazole,tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan,pyran, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine ringetc.

The 5- or 6-membered mono-heterocyclic aryl which is partially or fullysaturated and contains a hetero atom(s) selected from 1 to 4 nitrogen, 1to 2 oxygen and/or 1 to 2 sulfur atom(s) includes pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine,piperazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane,dithiolane, dithiane ring etc.

In the present invention, among the 3- to 15-membered mono-, bi- ortri-heterocyclic aryl which may be partially or fully saturated andcontains at least one nitrogen atom and opptionally 1 to 2 oxygen,and/or 1 to 2 sulfur atom(s), 3- to 15-membered mono-, bi- ortri-heterocyclic aryl containing at least one nitrogen atom andopptionally 1 to 2 oxygen, and/or 1 to 2 sulfur atom(s) includes, forexample, pyrrole, imidazole, triazole, tetrazole, pyrazole, indazole,purine, benzimidazole, benzazepine, benzotriazole, carbazole,β-carboline, phenothiazine, phenoxazine, perimidine etc.

The 3- to 15-membered mono-, bi- or tri-heterocyclic aryl which ispartially or fully saturated and contains at least one nitrogen atom andopptionally 1 to 2 oxygen, and/or 1 to 2 sulfur atom(s) includesaziridine, azetidine, azocane, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole(oxazolidine), dihydroisoxazole,tetrahydroisoxazole(isoxazolidine), dihydrothiazole,tetrahydrothiazole(thiazolidine), dihydroisothiazole,tetrahydroisothiazole(isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine,morpholine, thiomorpholine, indoline, isoindoline, dihydroindazole,perhydroindazole, dihydroquinoline, tetrahydroquinoline,perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline,perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine,perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine,perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnoline, dihydrobenzoxazine, dihydrobenzothiazine,pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole,dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole,perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine,dihydrobenzodiazepine, tetrahydrobenzodiazepine, dihydrobenzoxazepine,tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole,perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridineetc.

In the present invention, among the 5- to 7-membered mono-heterocyclicaryl which may be partially or fully saturated and contains at least onenitrogen atom and opptionally 1 to 2 oxygen, and/or 1 to 2 sulfuratom(s), 5- to 7-membered mono-heterocyclic aryl containing at least onenitrogen atom and opptionally 1 to 2 oxygen, and/or 1 to 2 sulfuratom(s) includes, for example, pyrrole, imidazole, triazole, tetrazole,pyrazole etc.

The 5- to 7-membered mono-heterocyclic aryl which is partially or fullysaturated and contains at least one nitrogen atom and opptionally 1 to 2oxygen, and/or 1 to 2 sulfur atom(s) includes pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole(oxazolidine), dihydroisoxazole,tetrahydroisoxazole(isoxazolidine), dihydrothiazole,tetrahydrothiazole(thiazolidine), dihydroisothiazole,tetrahydroisothiazole(isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine,tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine,tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole,tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine,tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine,morpholine, thiomorpholine etc.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylene, alkenylene, alkynylene group includes straight or branchedones. In addition, isomers on double bond, ring, fused ring (E-, Z-,cis-, trans-isomer), isomers generated from asymmetric carbon atom(s)(R—, S—, α-, β-isomer, enantiomer, diastereomer), optically activeisomers (D-, L-, d-, I-isomer), polar compounds generated bychromatographic separation (more polar compound, less polar compound),equilibrium compounds, rotamer, mixtures thereof at voluntary ratios andracemic mixtures are also included in the present invention.

According to the present invention, unless otherwise indicated and as isapparent for those skilled in the art, symbol

indicates that it is bound to the opposite side of the sheet (namelyα-configuration), symbol

indicates that it is bound to the front side of the sheet (namelyβ-configuration), symbol

indicates that it is α-configuration, β-configuration or a mixturethereof, and symbol

indicates that it is a mixture of α-configuration and βconfiguration.

The compound represented by formula (I) can be converted into apharmaceutically acceptable salt by known methods.

A pharmaceutically acceptable salt includes salt of alkali metal, saltof alkaline earth metal, ammonium salt, amine salt or acid addition saltetc.

The salt is preferably water-soluble. The suitable salt means, forexample, salt of alkali metal (potassium, sodium, lithium, etc.), saltof alkaline earth metal (calcium, magnesium, etc.), ammonium salt,pharmaceutically acceptable salt of organic amine (tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,N-methyl-D-glucamine, etc.).

The acid addition salt is preferably water-soluble. The suitable acidaddition salt means, for example, inorganic acid salt (hydrochloride,hydrobromate, hydroiodate, sulfate, phosphate, nitrate, etc.), ororganic acid salt (acetate, lactate, tartrate, benzoate, citrate,methane sulfonate, ethane sulfonate, benzene sulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.), etc.

The compound represented by formula (I) and the salt thereof may beconverted solvate.

The solvate is preferably non toxic and water-soluble. The suitablesolvate is, for example, solvate of water or alcohol (e.g., ethanol).

The compounds of the present invention represented by formula (I) may beconverted into the corresponding cyclodextrin clathrates by the methoddescribed in the specification of JP-B-50-3362, 52-31404 or 61-52146using α-, β- or γ-cyclodextrin or a mixture thereof. Converting into thecorresponding cyclodextrin clathrates serves to increase the stabilityand solubility in water of the compounds, and therefore it is useful inthe use for pharmaceuticals.

Among the compounds of formula (I), A is preferably A¹ or A², andparticularly preferably A².

Ring1 is preferably C3-10 mono- or bi-carbocyclic aryl which may bepartially or fully saturated, or 3- to 10-membered mono- orbi-heterocyclic aryl which may be partially or fully saturated andcontains a hetero atom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygenand/or 1 to 2 sulfur atom(s), and particularly preferably C3-7mono-carbocyclic aryl which may be partially or fully saturated, or 3-to 7-membered mono-heterocyclic aryl which may be partially or fullysaturated and contains a hetero atom(s) selected from 1 to 4 nitrogen, 1to 2 oxygen and/or 1 to 2 sulfur atom(s).

Most preferably, ring1 is C5 or 6 mono-carbocyclic aryl which may bepartially or fully saturated, or 5- or 6-membered mono-heterocyclic arylwhich may be partially or fully saturated and contains a hetero atom(s)selected from 1 to 4 nitrogen, 1 to 2 oxygen and/or 1 to 2 sulfuratom(s), and furan, thiophene, oxazole or benzene is most preferable ofall them.

Among the compounds of formula (I), D is preferably D¹ or D² andparticularly preferably D¹.

D¹ is preferably —COOH or —COOR².

D² is preferably —COO-Z¹-Z²-Z³.

Z¹ is preferably C1-15 alkylene, more preferably C1-8 alkylene andparticularly preferably C1-4 alkylene.

Z² is preferably —CO—, —OCO—, —COO—, —CONRZ¹, —OCONRZ⁷ or —OCOO—, andparticularly preferably —OCO—, —OCONRZ⁷ or —OCOO—.

Z³ is preferably C1-15 alkyl or C1-10 alkyl substituted by C1-10 alkoxy,C1-10 alkylthio, C1-10 alkyl-NRZ⁸- or ringZ, and particularly preferablyC4-12 alkyl.

Among the compounds of formula (I), T is preferably oxygen atom orsulfur atom, and particularly preferably oxygen atom.

Among the compounds of formula (I), X is preferably —CH₂—, —O— or —S—,and particularly preferably —CH₂—.

Among the compounds of formula (I), E is preferably E₂.

Among the compounds of formula (I), preferably compound is a compoundrepresented by formula (I-A):

(wherein all symbols have the same meanings as described above.),formula (I-B):

(wherein all symbols have the same meanings as described above.),formula (I-C):

(wherein all symbols have the same meanings as described above.),formula (I-D):

(wherein all symbols have the same meanings as described above.),formula (I-E):

(wherein all symbols have the same meanings as described above.) orformula (I-F):

(wherein all symbols have the same meanings as described above.).

Among the compounds of formula (I-A), preferably compound is a compoundrepresented by formula (I-A1):

(wherein G^(2A-1) is —Y^(a)-ring1-, Y^(a) is —S—, —SO₂—, —O— or —NR₁—,and other symbols have the same meanings as described above.).

Among the compounds of formula (I-A), particularly preferably compoundis a compound represented by formula (I-A1-a)

(wherein ring6 is C5 or 6 mono-carbocyclic aryl, or 5- or 6-memberedmono-heterocyclic aryl which may be partially or fully saturated andcontains a hetero atom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygen,and/or 1 to 2 sulfur atom(s), R¹⁰⁰ is a hydrogen atom or C1-4 alkyl, andother symbols have the same meanings as described above.).

Ring6 is particularly preferably furan, thiophene, oxazole, thiazole orbenzene, and concretely,

Among the compounds of formula (I-A), most preferably compound is acompound represented by formula (I-A1-a1):

(wherein, U^(1a-1) is C1-4 alkylene, C2-4 alkenyle or C2-4 alkynylene,U^(2a-1) is —O—, —S—, —SO—, —SO₂— or —NR¹²—, and other symbols have thesame meanings as described above.). A compound represented by formula(I-a1-1):

(wherein U^(3a-1) is C1-8 alkylene or ring 4, and other symbols have thesame meanings as described above.) or a compound represented by formula(I-a1-2):

(wherein all symbols have the same meanings as described above.) is mostpreferable of all them. tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dioxolane, dioxane, dithiolane, dithiane, dioxaindan, benzodioxane,chroman, benzodithiolane, benzodithiane ring etc.

In the present invention, C5-6 mono-carbocyclic aryl which may bepartially or fully saturated includes, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene,cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene,cycloheptadiene, benzene etc.

In the present invention, among the 3- to 7-membered mono-heterocyclicaryl which may be partially or fully saturated and contains a heteroatom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygen, and/or 1 to 2sulfur atom(s), 3- or 7-membered mono-heterocyclic aryl containing ahetero atom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygen, and/or 1 to2 sulfur atom(s) includes, for example, pyrrole, imidazole, triazole,tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran,thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole,thiazine, thiadiazine, thiazepine, thiadiazepine ring etc.

The 3- to 7-membered mono-heterocyclic aryl which is partially or fullysaturated and contains a hetero atom(s) selected from 1 to 4 nitrogen, 1to 2 oxygen and/or 1 to 2 sulfur atom(s) includes aziridine, azetidine,azocane, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline,triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine,tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane,oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole(oxazolidine),dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole,tetrahydrothiazole(thiazolidine),

(wherein all symbols have the same meanings as described above.) is mostpreferable of all them.

Moreover, a compound represented by formula (I-A1-a2):

(wherein ring7 is 3- to 15-membered mono-, bi- or tri-heterocyclic arylwhich may be partially or fully saturated and contains at least onenitrogen atom and optionally 1 to 2 oxygen, and/or 1 to 2 sulfuratom(s), n is an integer from 1 to 3. Other symbols have the samemeanings as described above.),

a compound represented by formula (I-A1-a3):

(wherein all symbols have the same meanings as described above.), or

a compound represented by formula (I-A1-a4):

(wherein all symbols have the same meanings as described above.) ispreferable.

Among compounds represented by formula (I-A1-a4), a compound representedby

(wherein all symbols have the same meanings as described above.) isparticularly preferable.

Particularly preferably, ring7 is 5- to 7-membered mono-heterocyclicaryl which may be partially or fully saturated and contains at least onenitrogen atom and opptionally 1 to 2 oxygen, and/or 1 to 2 sulfuratom(s).

Among compounds represented by formula (I-E), a compound represented byformula (I-E1):

(wherein all symbols have the same meanings as described above.), or acompound represented by formula (I-E2):

(wherein all symbols have the same meanings as described above.) ispreferable.

Moreover, a compound represented by formula (I-F):

(wherein all symbols have the same meanings as described above.),

a compound represented by formula (I-G):

(wherein all symbols have the same meanings as described above.), or

a compound represented by formula (I-H):

(wherein all symbols have the same meanings as described above.) ispreferable.

Among compounds represented by formula (I), compounds represented by

(wherein all symbols have the same meanings as described above.) isparticularly preferable.

(wherein all symbols have the same meanings as described above.) is mostpreferable.

As concrete compounds in present invention, compounds in following table1 to 68, compounds described in Example, and pharmaceutically acceptablesalts thereof and cyclodextrin clathrates thereof are given.

TABLE 1 (I-A-1)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 2 (I-A-2)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 3 (I-A-3)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 4 (I-A-4)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 5 (I-A-5)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 6 (I-A-6)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 7 (I-A-7)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 8 (I-A-8)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 9 (I-A-9)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 10 (I-A-10)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 11 (I-A-11)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 12 (I-A-12)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 13 (I-A-13)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 14 (I-A-14)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 15 (I-A-15)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 16 (I-A-16)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 17 (I-A-17)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 18 (I-A-18)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 19 (I-A-19)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 20 (I-A-20)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 21 (I-A-21)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 22 (I-A-22)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 23 (I-A-23)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 24 (I-A-24)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 25 (I-A-25)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 26 (I-A-26)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 27 (I-A-27)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 28 (I-A-28)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 29 (I-A-29)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 30 (I-A-30)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 31 (I-A-31)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 32 (I-A-32)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 33 (I-A-33)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 34 (I-A-34)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 35 (I-A-35)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 36 (I-A-36)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 37 (I-A-37)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 38 (I-A-38)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 39 (I-A-39)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 40 (I-A-40)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 41 (I-A-41)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 42 (I-A-42)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 43 (I-A-43)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 44 (I-A-44)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 45 (I-A-45)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 46 (I-A-46)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 47 (I-A-47)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 48 (I-A-48)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 49 (I-A-49)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 50 (I-A-50)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 51 (I-A-51)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 52 (I-A-52)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 53 (I-A-53)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 54 (I-A-54)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 55 (I-A-55)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 56 (I-A-56)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 57 (I-A-57)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 58 (I-A-58)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 59 (I-A-59)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 60 (I-A-60)

No. E  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

TABLE 61 (I-E-1)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 62 (I-E-2)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 63 (I-E-3)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 64 (I-E-4)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 65 (I-E-5)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 66 (I-E-6)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 67 (I-E-7)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 68 (I-E-8)

No. E 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

Processes for the Preparation of the Compound of the Present Invention

The compound represented by formula (I) can be prepared by the followingmethod or the method described in Example.

-   1. Among the compounds represented by formula (I), a compound in    which T represents oxygen atom, and X represents —CH₂—, i.e., a    compound represented by formula (IA):

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA) can be prepared by reductiveamination of the compounds of formula (II):

(wherein R¹⁸ is C1-10 alkyl and E′ has the same meaning as E. With theproviso that, hydroxyl, amino, carboxy or formyl in the grouprepresented by E′ may be protected, if necessary.) and a compoundrepresented by formula (III):

(wherein A′ and D′ have the same meanings as A and D, respectively. Withthe proviso that, hydroxyl, amino, carboxy or formyl in the grouprepresented by A′ and D′ may be protected, if necessary.), if necessary,followed by removal of the protective group from the resulting product.

The reductive amination is well known. For example, it may be carriedout in an organic solvent (e.g., methanol, ethanol, dichloromethane,tetrahydrofuran, dimethoxyethane, diethyl ether) in the presence ofreducing agent (e.g., sodium cyanoborohydride, sodium borohydride,sodium triacetoxyborohydride, pyridine borane) at 0 to 100° C.

The removal of the protective group may be carried out by followingmethod.

The reaction for removing the protective group for carboxy, hydroxy,amino or formyl is well known, including, for example, the following:

-   (1) alkali hydrolysis,-   (2) deprotection under acidic condition,-   (3) deprotection through hydrogenolysis,-   (4) silyl deprotection,-   (5) deprotection with metal,-   (6) deprotection with organic metal.

These methods are described concretely.

-   (1) The deprotection through alkali hydrolysis may be effected, for    example, in an organic solvent (e.g., methanol, tetrahydrofuran,    dioxane) by the use of an alkali metal hydroxide (e.g., sodium    hydroxide, potassium hydroxide, lithium hydroxide), an alkaline    earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide) or    a carbonate (e.g., sodium carbonate, potassium carbonate), or an    aqueous solution thereof or their mixture, at 0 to 40° C.-   (2) The deprotection under acidic condition may be effected, for    example, in an organic solvent (e.g., dichloromethane, chloroform,    dioxane, ethyl acetate, anisole) with an organic acid (e.g., acetic    acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic    acid) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid)    or their mixture (hydrogen bromide/acetic acid), at 0 to 100° C.-   (3) The deprotection through hydrogenolysis may be effected, for    example, in a solvent (e.g., ether-type (e.g., tetrahydrofuran,    dioxane, dimethoxyethane, diethyl ether), alcohol-type (e.g.,    methanol, ethanol), benzene-type (e.g., benzene, toluene),    ketone-type (e.g., acetone, methyl ethyl ketone), nitrile-type    (e.g., acetonitrile), amide-type (e.g., dimethylformamide), water,    ethyl acetate, acetic acid, or mixed solvent of two or more of    these), in the presence of a catalyst (e.g., palladium-carbon,    palladium-black, palladium hydroxide, platinum oxide, Raney nickel),    in a hydrogen atmosphere under a normal pressure or increased    pressure or in the presence of ammonium formate, at 0 to 200° C.-   (4) The silyl deprotection may be effected, for example, in a    water-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile)    by the use of tetrabutylammonium fluoride, at 0 to 40° C.-   (5) The deprotection with metal may be effected, for example, in an    acidic solvent (acetic acid, buffer having pH 4.2 to 7.2, or mixture    of their solution with organic solvent such as tetrahydrofuran) in    the presence of zinc powder with or without ultrasonic waves applied    thereto, at 0 to 40° C.-   (6) The deprotection with metal complex may be effected, for    example, in an organic solvent (e.g., dichloromethane,    dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile,    dioxane, ethanol), water or their mixed solvent, in the presence of    a trapping reagent (e.g., tributyltin hydride, triethylsilane,    dimedone, morpholine, diethylamine, pyrrolidine), an organic acid    (e.g., acetic acid, formic acid, 2-ethylhexanoic acid) and/or an    organic acid salt (e.g., sodium 2-ethylhexanoate, potassium    2-ethylhexanoate), in the presence or absence of a phosphine-type    reagent (e.g., triphenyl phosphine), by the use of a metal complex    (tetrakistriphenylphosphine palladium(O),    dichlorobis(triphenylphosphine) palladium(II), palladium(II)    acetate, chlorotris(triphenylphosphine) rhodium(I)), at 0 to 40° C.

Apart from the above, the deprotection may also be effected, forexample, according to the methods described in T. W. Greene, ProtectiveGroups in Organic Synthesis, Wiley, New York, 1999.

The intended compounds of the invention may be readily produced throughselective use of the deprotecting reaction, which could be readilyunderstood by anyone skilled in the art.

The carboxyl-protective group includes, for example, methyl, ethyl,allyl, t-butyl, trichloroethyl, benzyl (Bn), and phenacyl etc.

The hydroxyl-protective group includes, for example, methyl, trityl,methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM),2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBDMS), t-butyidiphenylsilyl (TBDPS), acetyl (Ac),pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl(Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc) etc.

The amino-protective group includes, for example, benzyloxycarbonyl,t-butoxycarbonyl, allyloxycarbonyl (Alloc),1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl,benzyloxymethyl (BOM), and 2-(trimethylsilyl)ethoxymethyl (SEM) etc.

The formyl-protective group is, for example, acetal (e.g.,dimethylacetal) etc.

The carboxy, hydroxy, amino or formyl-protective may be any others thanthose mentioned above, capable of being readily and selectively removed,and are not specifically defined. For example, those described in T. W.Greene, Protective Groups in Organic Synthesis, 3rd Ed., Wiley, NewYork, 1999 may be used.

-   2. The compounds represented by formula (IA) can be prepared by    reductive amination of the compounds of formula (IV):

(wherein all symbols have the same meanings as defined above.) and thecompounds of formula (V):

(wherein A^(a) is A^(1a) or A^(2a), A^(1a) is 1) C1-7 straight-chainalkylene optionally substituted by 1 to 2 C1-4 alkyl(s), 2) C2-7straight-chain alkenylene optionally substituted by 1 to 2 C1-4alkyl(s), or 3) C2-7 straight-chain alkynylene optionally substituted by1 to 2 C1-4 alkyl(s), A^(2a), is -G^(1a)-G^(2a)-G³-, G^(1a) is 1) C1-3alkylene optionally substituted by 1 to 2 C1-4 alkyl(s), 2) C2-3alkenylene optionally substituted by 1 to 2 C1-4 alkyl(s), or 3) C2-3alkynylene optionally substituted by 1 to 2 C1-4 alkyl(s), G^(2a) hasthe same meaning as G². With the proviso that, hydroxyl, amino, carboxyor formyl in the group represented by G²a may be protected, ifnecessary. Other symbols have the same meanings as defined above), ifnecessary, followed by removal of the protective group from theresulting product.

The reductive amination and the removal of the protective group may becarried out by the above method.

-   3. Among the compounds represented by formula (I), a compound in    which T represents oxygen atom, and X represents —O—, i.e., a    compound represented by formula (IB):

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compounds represented by formula (IB) can be prepared by cyclizationof the compounds of formula (VI):

(wherein all symbols have the same meanings as defined above.), ifnecessary, followed by removal of the protective group from theresulting product.

The cyclization is well known. For example, it may be carried out in anorganic solvent (e.g., tetrahydrofuran, dichloromethane,dimethoxyethane, diethyl ether, dimethylformamide) in the presence of abase (e.g., triethylamine, pyridine, potassium carbonate, sodiumbicarbonate) with carbonylation agent (e.g., triphosgene,1,1′-carbonyldiimidazole (CDI), phosgene) at 0 to 50° C.

The removal of the protective group may be carried out by the abovemethod.

-   4. Among the compounds represented by formula (I), a compound in    which T represents oxygen atom, and X represents —S—, i.e., a    compound represented by formula (IC):

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compounds represented by formula (IC) can be prepared by cyclizationof the compounds of formula (VII):

(wherein all symbols have the same meanings as defined above.), ifnecessary, followed by removal of the protective group from theresulting product.

The cyclization and the removal of the protective group may be carriedout by the above method.

-   5. Among the compounds represented by formula (I), a compound in    which T represents sulfur atom, i.e., a compound represented by    formula (ID):

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compounds represented by formula (ID) can be prepared bythioamidation of the compounds of formula (VIII):

(wherein all symbols have the same meanings as defined above.), ifnecessary, followed by removal of the protective group from theresulting product.

The thioamidation is well known. For example, it may be carried out inan organic solvent (e.g., toluene, diethyl ether, methylene chloride,chloroform, dioxane, tetrahydrofuran) in the presence of a thyonationagent (e.g., Lawesson's Reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide),phosphorus pentoxide) at 0 to 150° C.

The removal of the protective group may be carried out by the abovemethod.

-   6. Among the compounds represented by formula (I), a compound in    which D represents —CH₂OH, i.e., a compound represented by formula    (IE):

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compounds represented by formula (IE) can be prepared by reductionof the compounds of formula (IX):

(wherein all symbols have the same meanings as defined above.), ifnecessary, followed by removal of the protective group from theresulting product.

The reduction is well known. For example, it may be carried out in anorganic solvent (e.g., tetrahydrofuran, dimethoxyethane, diethyl ether,dimethylformamide, dioxane, methanol, ethanol, isopropanol) or anaqueous solution thereof in the presence of a reducing agent (e.g.,sodium borohydride, lithium borohydride) at 0 to 70° C.

The removal of the protective group may be carried out by the abovemethod.

-   7. Among the compounds represented by formula (I), a compound in    which D represents —CONR³SO₂R⁴, —CONR⁶R⁷, —CONR⁶SO₂R⁸ or    —CO—(NH-amino acid residue-CO)_(m)—OH, i.e., a compound represented    by formula (IF):

(wherein D^(a) is —CONR³SO₂R⁴, —CONR⁶R⁷, —CONR⁶SO₂R⁸ or —CO—(NH-aminoacid residue-CO)_(m)—OH and other symbols have the same meanings asdescribed above.) can be prepared by the following method.

The compounds represented by formula (IF) can be prepared by amidationof the compounds of formula (X):

(wherein all symbols have the same meanings as defined above.) and thecompounds of formula (XI-1):H—NR³SO₂R⁴  (XI-1)(wherein all symbols have the same meanings as defined above.), thecompounds of formula (XI-2):H—NR⁶R⁷  (XI-2)(wherein all symbols have the same meanings as defined above.), thecompounds of formula (XI-3):H—NR⁶SO₂R⁸  (XI-3)(wherein all symbols have the same meanings as defined above.), or thecompounds of formula (XI-4):H—(NH-amino acid residue-CO)m—OH  (XI-4)(wherein all symbols have the same meanings as defined above. With theproviso that, amino, hydroxy or carboxy in the compounds represented byformula (XI-4) may be protected, if necessary.), if necessary, followedby removal of the protective group from the resulting product.

The method via an acyl halide may be carried out, for example, byreacting carboxylic acid with an acyl halide (e.g., oxalyl chloride orthionyl chloride etc.) in an organic solvent (e.g., chloroform,dichloromethane, diethyl ether or tetrahydrofuran) or without a solventat −20° C. to reflux temperature. And then the obtained acyl halidederivative may be reacted with amine in an inert organic solvent (e.g.,chloroform, dichloromethane, diethyl ether or tetrahydrofuran) in thepresence of a base (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine or dilsopropylethylamine etc.) at 0 to 40° C. Asan alternative, the obtained acyl halide derivative may be reacted in anorganic solvent (e.g., dioxane, tetrahydrofuran) using an alkalineaqueous solution (e.g., sodium bicarbonate, sodium hydroxide) at 0 to40° C.

The method using a condensing agent may be carried out, for example, byreacting carboxylic acid with amine in an organic solvent (e.g.,chloroform, dichloromethane, dimethylformamide, diethyl ether ortetrahydrofuran) or without a solvent, in the presence or absence of abase (e.g., pyridine, triethylamine, dimethylaniline ordimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide(EDC), 1,1′-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,or 1-propanephosphonic acid cyclic anhydride (PPA)), in the presence orabsence of 1-hydroxybenzotiazole (HOBt), at 0 to 40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g., argon, nitrogen) to avoid water in order to obtain apreferable result.

The removal of the protective group may be carried out by the abovemethod.

-   8. Among the compounds of the present invention represented by    formula (I), a compound in which D represents —O—(CO-amino acid    residue-NH)_(m)—H or —OCO—R¹⁰, i.e., a compound represented by    formula (IG):

(wherein D^(b) is —O—(CO-amino acid residue-NH)_(m)—H or —OCO—R¹⁰ andother symbols have the same meanings as described above.) can beprepared by the following method.

The compounds represented by formula (IG) can be prepared by esterifyingthe compounds of formula (XII):

(wherein D^(c) is —OH or —CH₂OH and other symbols have the same meaningsas described above.) with the compounds of formula (XIII-1):HO—(CO-amino acid residue-NH)_(m)—H  (XIII-1)(wherein all symbols have the same meanings as defined above. With theproviso that, amino, hydroxy or carboxy in the compounds represented byformula (XIII-1) may be protected, if necessary.) or the compounds offormula (XIII-2):HO₂C—R¹⁰  (XIII-2)(wherein R¹⁰ has the same meaning as defined above.), if necessary,followed by removal of the protective group from the resulting product.

The method of esterification is known. For example, it includes themethod

-   (1) via an acyl halide,-   (2) via a mixed acid anhydride,-   (3) using a condensing agent.

These methods are explained as follows.

-   (1) The method via an acyl halide may be carried out, for example,    by reacting carboxylic acid with an acid-halogenating agent (e.g.,    oxalyl chloride or thionyl chloride etc.) in an organic solvent    (e.g., chloroform, dichloromethane, diethyl ether or    tetrahydrofuran) or without a solvent at −20° C. to reflux    temperature. And then the obtained acyl halide derivative may be    reacted with alcohol in an inert organic solvent (e.g., chloroform,    methylene chloride, diethyl ether or tetrahydrofuran) in the    presence of a base (e.g., pyridine, triethylamine, dimethylaniline,    dimethylaminopyridine or diisopropylethylamine etc.) at 0 to 40° C.    As an alternative, the obtained acyl halide derivative may be    reacted in an organic solvent (e.g., dioxane, tetrahydrofuran) using    an alkaline aqueous solution (e.g., sodium bicarbonate, sodium    hydroxide) at 0 to 40° C.-   (2) The method via a mixed acid anhydride may be carried out, for    example, by reacting carboxylic acid with an acyl halide (e.g.,    pivaloyl chloride, tosyl chloride or mesyl chloride) or an acid    derivative (ethyl chloroformate or isobutyl chloroformate) in an    organic solvent (e.g., chloroform, dichloromethane, diethyl ether,    tetrahydrofuran) or without a solvent, in the presence of a base    (e.g., pyridine, triethylamine, dimethylaniline,    dimethylaminopyridine or diisopropylethylamine) at 0 to 40° C. And    then the obtained mixed acid anhydride derivative may be reacted    with alcohol in an organic solvent (e.g., chloroform,    dichloromethane, diethyl ether or tetrahydrofuran), at 0 to 40° C.-   (3) The method using a condensing agent may be carried out, for    example, by reacting carboxylic acid with alcohol in an organic    solvent (e.g., chloroform, dichloromethane, dimethylformamide,    diethyl ether or tetrahydrofuran) or without a solvent, in the    presence or absence of a base (e.g., pyridine, triethylamine,    dimethylaniline or dimethylaminopyridine), using a condensing agent    (e.g., 1,3-dicyclohexyl carbodiimide (DCC),    1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide (EDC),    1,1′-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,    1-propanephosphonic acid cyclic anhydride (PPA)), in the presence or    absence of 1-hydroxybenzotiazole (HOBt), at 0 to 40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g., argon, nitrogen) to avoid water in order to obtain apreferable result.

The removal of the protective group may be carried out by the abovemethod.

-   9. Among the compound of the present invention represented by    formula (I), a compound in which D represents formyl, i.e., a    compound represented by formula (IH)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compounds represented by formula (IH) can be prepared by oxidizingthe compounds of formula (XIV):

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protective group.

The reaction for oxidation is known, for example, including thefollowing:

-   (1) Swern oxidation,-   (2) oxidation with Dess-Martin reagent,-   (3) oxidation with TEMPO reagent.

These methods are described concretely.

-   (1) The method of Swern oxidation comprises, for example, reacting    oxalyl chloride with dimethyl sulfoxide in an organic solvent (e.g.,    chloroform, dichloromethane) at −78° C., and then reacting the    resulting solution with the alcohol compound, and further with a    tertiary amine (e.g.; triethylamine, N,N-diisopropylethylamine,    N-methylmorpholine, N-ethylpiperidine,    diazabicyclo[5.4.0]undec-7-ene) at −78 to 20° C.-   (2) The method with a Dess-Martin reagent comprises, for example,    processing the compound in an organic solvent (e.g., chloroform,    dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile,    t-butyl alcohol) in the presence of a Dess-Martin reagent    (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one), in the    presence or absence of a base (e.g., pyridine) at 0 to 40° C.-   (3) The method with a TEMPO reagent comprises, for example,    processing the compound in an organic solvent (e.g., chloroform,    dichloromethane, tetrahydrofuran, toluene, acetonitrile, ethyl    acetate, water) or in a mixed solvent thereof, in the presence of a    TEMPO reagent (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical)    and a re-oxidizing agent (e.g., aqueous hydrogen peroxide, sodium    hypochlorite, 3-chloroperbenzoic acid, iodobenzene diacetate,    potassium peroxymonosulfate (Oxon, trade name)), in the presence or    absence of a quaternary ammonium salt (e.g., tetrabutylammonium    chloride, tetrabutylammonium bromide), in the presence or absence of    an inorganic salt (e.g., sodium bromide, potassium bromide), in the    presence or absence of an inorganic base (e.g., sodium    hydrogencarbonate, sodium acetate), at 20 to 60° C.

The oxidation is not limited to the above, and may be any other capableof readily and selectively oxidizing the alcohol into a ketone. Forexample, herein employable is any of Johns oxidation, oxidation with PCC(pyridinium chlorochromate), oxidation with sulfur trioxide-pyridinecomplex, or those described in Comprehensive Organic Transformations(Richard C. Larock, VCH Publishers, Inc., (1989), pp. 604-614).

-   10. Among the compound of the present invention represented by    formula (I), a compound in which D represents —COOR², —COOR⁹ or    —COO-Z¹-Z²-Z³-, i.e., a compound represented by formula (IJ):

(wherein D^(d) is —COOR², —COOR⁹ or —COO-Z¹-Z²-Z³-, and other symbolshave the same meanings as described above.) can be prepared by thefollowing method.

The compounds represented by formula (IJ) can be prepared esterifyingthe compounds of formula (X):

(wherein all symbols have the same meanings as defined above.) with thecompound of formula (XV-1):R¹⁹—R²  (XV-1)(wherein R¹⁹ is hydroxy or halogen atom, and other symbols have the samemeanings as defined above.), the compounds of formula (XV-2):R¹⁹—R⁹  (XV-2)(wherein all symbols have the same meanings as defined above.) or thecompounds of formula (XV-3):R¹⁹-Z^(1a)-Z^(2a)-Z^(3a)  (XV-3)(wherein Z^(1a), Z^(2a) and Z^(3a) are Z¹, Z² and Z³, respectively. Withthe proviso that, hydroxy, amino, carboxy or formyl in the groupsrepresented by Z^(1a)-Z^(2a)-Z^(3a) may be protected, if necessary.) ifnecessary, followed by removal of the protective group.

The esterification with the compound of formulae (XI-1), (XI-2) and(XI-3) in which R¹⁷ is hydroxyl may be effected in the same manner asabove.

The esterification with the compound of formulae (XI-1), (XI-2) and(XI-3) in which R¹⁷ is halogen may be carried out, for example, in anorganic solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane,diethyl ether, dimethylacetamide), in the presence of a base (e.g.,potassium carbonate, cesium carbonate, sodium carbonate, potassiumhydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodiumhydroxide) at 0 to 150° C.

The removal of the protective group may be carried out by the methodsdescribed above.

The compounds represented by formulae (II), (III), (IV), (V), (VI),(VII), (XI-1), (XI-2), (XI-3), (XI-4), (XIII-1), (XIII-2), (XV-1),(XV-2) and (XV-3) are known compounds or can be prepared by knownmethods.

For example the compounds of formulae (VI) and (VII) can be prepared bythe method described in reaction scheme 1.

In the reaction scheme 1, R²⁰ represents the protecting group ofhydroxy, Ac represents an acetyl group, and other symbols have the samemeanings as defined above.

In the reaction scheme 1, the compound of formula (XVI) used as thestarting material is known compound or can be prepared easily by knownmethods.

-   11. Among the compounds represented by formula (I), a compound in    which T is oxygen atom, E is E², E² is U——U²—U³, U¹ is methylene and    U² is —NH—, i.e., a compound (IK):

(wherein all symbols have the same meanings as defined above.) can beprepared by the following method.

The compounds represented by formula (IK) can be prepared by reductiveamination of the compounds of formula (XIX):

(wherein all symbols have the same meanings as defined above.) and thecompounds of formula (XX):H₂N—U³  (XX)(wherein U³ has the same meaning as U³. With the proviso that, hydroxyl,amino, carboxyl or formyl in the group represented by U^(3′)may beprotected, if necessary. Other symbols have the same meanings as definedabove.), if necessary, followed by removal of the protecting group.

The reductive amination and the removal of the protective group may becarried out by the methods described above.

-   12. Among the compounds represented by formula (I), a compound in    which T is oxygen atom, A is A², A² is G′-G²-G³, G¹ is C1-4    alkylene, G² is —Y—, —Y-ring1- or —Y— C1-4 alkylene-ring1-, Y is    —S—, E is E², E² is U¹—U²—U³, U¹ is methylene, and U²—O—, i.e. a    compound represented by formula (IL):

(wherein A^(b) is -G^(1a)G^(2a)-G³-, G^(1a) is C1-4 straight-chainalkylene, G^(2a) is —S—, —S-ring1- or —S—C1-4 alkylene-ring1-, and othersymbols have the same meanings as defined above) can be prepared by thefollowing method.

The compounds represented formula (IL) can be prepared by reacting thecompound of formula (XXI):

(wherein R²¹ is C1-3 alkylene, and other symbols have the same meaningsas defined above.) with the compounds of formula (XXII):R²²—R²³-G³-D  (XXII)(wherein R²² is halogen atoms, R²³ is bond, -ring1- or-C1-4alkylene-ring1-. With the proviso that, hydroxy, amino, carboxy orformyl in the group represented by R²³ may be protected, if necessary.Other symbols have the same meanings as defined above.), if necessary,followed by removal of the protecting group.

The reaction is known. For example, it may be carried out in an organicsolvent (e.g., ethanol, methanol, tetrahydrofuran, dichloromethane,dimethylformamide) using a base (e.g., sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium methylate, diethylamine) at 0 to 40°C.

The removal of the protective group may be carried out by the methodsdescribed above.

The compounds represented by formulae (XX) and (XXII) are knowncompounds or can be prepared by known methods readily.

The compounds of formulae (XIX) and (XXI) can be prepared by the methoddescribed in the reaction scheme 2, 3 and 4.

In the reaction scheme 2, 3 and 4, R²⁴ represents a hydrogen atom or

R²⁵ is the protecting group of hydroxy, Et is ethyl, Boc ist-butoxycarbonyl, and other symbols have the same meanings as definedabove.

In the reaction schemes 2, 3 and 4, the compound of formula (XXIII) usedas the starting materials and the compounds of formulae (XXX), (XXXIV)and (XXXVIII) are known compounds or can be prepared easily by knownmethods.

In each reaction described herein, the reaction product can be purifiedby general purification techniques such as distillation under ordinarypressure or a reduced pressure, high performance liquid chromatography,thin layer chromatography or column chromatography using silica gel ormagnesium silicate, washing and recrystallization. Purification may becarried out in each reaction or after completion of several reactions.

Pharmacological Activity of the Compounds of the Invention:

For example, the pharmacological activities of the compounds of theinvention were confirmed in experiments performed in a laboratory usingthe cells which express prostanoid receptor sub-types.

(i) Experiment for Receptor-Binding Using Cells Which Express ProstanoidReceptor Sub-Types

According to the method of Sugimoto et al. (J. Biol. Chem., 267,6463-6466 (1992)), CHO cells which expressed prostanoid receptorsub-types (murine EP₁, EP₂, EP_(3α), and EP₄, respectively) wereprepared and used as membrane authentic samples.

A reaction solution (200 μl) containing the prepared membrane fraction(0.5 mg/ml) and ³H-PGE₂ was incubated at room temperature for 1 hour.The reaction was terminated with ice cold buffer (3 ml), and thereaction mixture was filtered under suction through a glass filter(GF/B), on which the binding ³H-PGE₂ was trapped, and the bindingradioactivity was measured by means of a liquid scintillator.

The Kd value was obtained from the Scatchard plots [Ann. N.Y. Acad.Sci., 51, 660 (1949)]. Non-specific binding was obtained as the bindingin the presence of an excess amount (2.5 μM) of unlabelled PGE₂.Measurement of the binding inhibition for ³H-PGE₂ with the compounds ofthe present invention was performed by adding ³H-PGE₂ (2.5 nM) and aseries of concentrations of the compound of the present invention. Inthis reaction, the following buffer was used in all cases.

-   Buffer: 10 mM potassium phosphate (pH 6.0), 1 mM EDTA, 10 mM MgCl₂,    and 0.1M NaCl.

Dissociation constant Ki (μM) of each compound was calculated from thefollowing equation.Ki=IC₅₀/(1+([C]/Kd))

-   IC₅₀: The concentration of the compound of the present invention    which inhibits half of the specific binding of [³H]PGE₂-   C: The concentration of [³H]PGE₂-   Kd: The dissociation constant of [³H]PGE₂

The binding activity (Ki) of the compound prepared in Example 4(1) tothe mouse EP₂ receptor was 14 nM.

-   Toxicity:

The toxicity of the compounds of the present invention represented byformula (I) is very low and therefore the compounds may be consideredsafe for pharmaceutical use.

INDUSTRIAL APPLICABILITY

Application to Pharmaceutical Preparations:

The compounds of the present invention bind to EP₂ subtype of PGEreceptor specifically and strongly and it is considered that they arerelated to inhibition of TNF-α production and enhancement of IL-10production. Therefore it is considered that the compounds which bind toEP₂ receptor are useful for prevention and/or treatment of immunediseases (e.g., autoimmune diseases such as amyotrophic lateralsclerosis (ALS), multiple sclerosis, Sjogren's syndrome, rheumatoidarthritis and systemic lupus erythematosus etc., and rejection afterorgan transplantation), allergic diseases (e.g., asthma, allergicrhinitis, allergic conjunctivitis, atopic dermatitis, food allergy),neuronal cell death, dysmenorrhea, premature birth, abortion, baldness,retinal neuropathy such as glaucoma, erectile dysfunction, arthritis,pulmonary injury, pulmonary fibrosis, pulmonary emphysema, bronchitis,chronic obstructive pulmonary disease, hepatic injury, acute hepatitis,liver cirrhosis, shock, nephritis (acute nephritis, chronic nephritis),renal failure, circulatory diseases (e.g., hypertension, myocardialischemia, chronic arterial obstruction, vibration disease), systemicinflammatory response syndrome, sepsis, hemophagocytosis syndrome,macrophage activation syndrome, still disease, Kawasaki Disease, burn,systemic granuloma, ulcerative colitis, Crohn disease, hypercytokinemiaat dialysis, multiple organ failure, and bone diseases (e.g., fracture,refracture, intractable fracture, nonunion, pseudarthrosis,osteomalacia, Paget's disease of bone, ankylosing spondylitis, bonemetastasis, osteroarthritis and destruction of bone/cartilage due tothese analogous diseases) etc. It is also considered that the compoundsare useful as an agent for accelerating the osteogenesis/cure after bonesurgery (e.g., fracture, bone graft, artificial arthrogenesis, spinalfusion, surgery for multiple myeloma, lung cancer, breast cancer, etc.,other bone repair) or substitute treatment for bone grafting. It isfurther considered that the compounds are useful agents for acceleratingthe regeneration of peridontium in periodontal disease etc.

Among the compounds represented by formula (I) are those which bind toEP₄ receptor as well as EP₂ receptor. It is considered that thecompounds which bind to EP₄ receptor are useful for prevention and/ortreatment of immune diseases (e.g., autoimmune diseases such asamyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren'ssyndrome, rheumatoid arthritis and systemic lupus erythematosus etc.,and rejection after organ transplantation), asthma, neuronal cell death,arthritis, pulmonary injury, pulmonary fibrosis, pulmonary emphysema,bronchitis, chronic obstructive pulmonary disease, hepatic injury, acutehepatitis, nephritis (acute nephritis, chronic nephritis), renalfailure, hypertension, myocardial ischemia, systemic inflammatoryresponse syndrome, sepsis, hemophagocytosis syndrome, macrophageactivation syndrome, still disease, Kawasaki Disease, burn, systemicgranuloma, ulcerative colitis, Crohn disease, hypercytokinemia atdialysis, multiple organ failure and shock etc. EP₄ receptor also takespart in mucous membrane protective action and thus is considered usefulfor prevention and/or treatment of digestive tract ulcer such as gastriculcer and duodenal ulcer and stomatitis. EP₄ receptor further takes partin trichogenous action and hair growing action and is considered usefulfor prevention and/or treatment of baldness and alopecia etc. Moreover,EP₄ receptor takes part in maturation of cervical canal and thus isconsidered useful as a cervical canal maturing agent.

Furthermore, the compound bound to EP₄ receptor has an osteogenesisaccelerating action and thus is considered not only useful forprevention and/or treatment of bone diseases in which the amount of boneis decreased, e.g., 1) primary osteoporosis due to, e.g., aging,menopause, overietomy, 2) secondary osteoporosis (e.g.,glucocorticoid-induced osteoporosis, hyperhyroidismic osteoporosis,fixed induced osteoporosis, heparin-induced osteoporosis,immunosuppression-induced osteoporosis, osteoporosis due to renalinsufficiency, inflammatory osteoporosis, osteoporosis due to Cushing'ssyndrome, rheumatic osteoporosis), 3) bone diseases such as transfer ofcancer to bone, hypercalcemia, Behcet's disease, bone deficiency (e.g.,alveolar bone deficiency, mandible deficiency, infantile idiopathic bonedeficiency) and osteonecrosis but also useful as a agent foraccelerating the osteogenesis/treatment after bone surgery (e.g.,fracture, bone graft, artificial arthrogenesis, spinal fusion, otherbone repair) or substitute for bone transfer.

Moreover, EP₄ acts to induce physiologic sleep and inhibit plateletaggregation and the compound bound to EP₄ receptor is considered usefulfor prevention of somnipathy and thrombosis.

The compound connected both to EP₂ receptor and EP₄ receptor can beexpected to exert an additive or synergistic effect on diseases relatedto both the receptors.

The compound represented by formula (I) or pharmaceutically acceptablesalt thereof may be administered in combination with otherpharmaceutical preparations to accomplish the following purposes:

-   1) To complement for and/or enhance the preventive and/or treatment    effect of the compound to be combined;-   2) To improve the kinetics/absorption of the compound to be combined    and reduce the dose of the compound; and/or-   3) To eliminate the side effect of the compound to be combined

The compound represented by formula (I) and other pharmaceuticalpreparations may be administered in the form of formulation having thesecomponents incorporated in one preparation or may be administered inseparate preparations. In the case where these pharmaceuticalpreparations are administered in separate preparations, they may beadministered simultaneously or at different times. In the latter case,the compound represented by formula (I) may be administered before theother pharmaceutical preparations. Alternatively, the otherpharmaceutical preparations may be administered before the compoundrepresented by formula (I). The method for the administration of thesepharmaceutical preparations may be the same or different.

The diseases on which the preventive and/or treatment effect of theaforementioned combined preparations works are not specifically limitedbut may be those for which the preventive and/or treatment effect of thecompound represented by formula (I) is complemented and/or enhanced.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on bone diseases include, for example,phosphodiesterases-4 inhibitor, bisphosphonate preparation, vitamin Dpreparation, calcium adjuvant, estrogen preparation, calcitoninpreparation, isoflavone-based preparation, anabolic steroid preparation,vitamin K preparation, cathepsin K inhibitor, prostaglandins, statin,parathyroid hormone, and growth factors etc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on chronic obstructive lung diseases and/orasthma include, for example, phosphodiesterases-4 inhibitor, steroids, βadrenoreceptor stimulant, leukotriene receptor antagonist, thromboxanesynthesis enzyme inhibitor, thromboxane A₂ receptor antagonist, mediatorrelease inhibitor, antihistamines, xanthine derivatives, anticholinergicpreparation, cytokine inhibitor, prostaglandins, forskolin preparation,elastase inhibitor, metaprotease inhibitor, expectorant, and antibioticetc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on dysmenorrhea include, for example,analgesic (nonsteroidal anti-inflammatory drug (NSAID), cyclooxygenase(COX) inhibitor etc.), oral contraceptive, hormone preparation,antispasmodic, β adrenoreceptor stimulant, Vasopressin V1a antagonist,prostaglandin synthetase inhibitor, local anesthetic, calcium channelblocker, potassium channel blocker, leukotriene receptor antagonist,smooth muscle relaxant, vasodilator etc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on arthritis or rheumatoid arthritis include,for example, metaprotease inhibitor, immunosuppressant, nonsteroidalanti-inflammatory drug (NSAID), steroids, phosphodiesterases-4 inhibitoretc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on erectile dysfunction include, for example,phosphodiesterases-5 inhibitor etc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on shock include, for example, elastaseinhibitor etc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on colitis include, for example, nitric oxidesynthase inhibitor, poly(ADP-ribose)polymerase, phosphodiesterases-4inhibitor, elastase inhibitor, interleukin 8 antagonist etc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on acute nephritis and chronic nephritisinclude, for example, steroids, phosphodiesterases-4 inhibitor,nonsteroidal anti-inflammatory drug, thromboxane A₂ receptor antagonist,leukotriene receptor antagonist, angiotensin II antagonist, angiotensinconverting enzyme inhibitor, diuretic etc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on hypertension include, for example, calciumchannel blocker, angiotensin II antagonist, angiotensin convertingenzyme inhibitor, phosphodiesterases-4 inhibitor, diuretic etc.

Examples of the phosphodiesterases-4 inhibitor include, for example,rolipram, cilomilast (trade name: Ariflo), Bay 19-8004, NIK-616,cilomilast (BY-217), cipamfylline (BGL-61063), atizolam (CP-80633),SCH-351591, YM-976, V-11294A, PD-168787, D-4386, and IC-485 etc.

Examples of the phosphodiesterases-5 inhibitor include, for example,sildenafil etc.

Examples of the bisphonate preparation include, for example, sodiumalendronate, disodium chlodronate, disodium pamidronate, disodiumethydronate, ivandronate, disodium incadronate, minodronate,olpadronate, sodium risedronate, tildronate, and zoledronate etc.

Examples of the calcitonin preparation include, for example, calcitonin,and elcatonin etc.

Examples of the prostaglandins (hereinafter abbreviated as “PG”) includePG receptor agonist, and PG receptor antagonist.

Examples of PG receptor include PGE receptors (EP₁, EP₂, EP₃, EP₄), PGDreceptors (DP), PGF receptors (FP), and PGI receptors (IP) etc.

Examples of the steroids for external application include, for example,clobetasol propionate, diflorasone acetate, fluocinonide, mometasonefuroate, betamethasone dipropionate, betamethasone butyrate propionate,betamethasone valerate, difluprednate, budesonide, diflucortolonevalerate, amcinonide, halcinonide, dexamethasone, dexamethasonepropionate, dexamethasone valerate, dexamethasone acetate,hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyratepropionate, deprodone propionate, prednisolone valerate acetate,fluocinolone acetonide, beclomethasone dipropionate, triamcinoloneacetonide, flumethasone pivalate, alclometasone dipropionate,clobetasone butyrate, beclomethasone propionate and fludroxycortide etc.

Examples of the steroid preparation for internal use or injectioninclude cortisone acetate, hydrocortisone, hydrocortisone sodiumphosphate, hydrocortisone sodium succinate, fludrocortisone acetate,prednisolone, prednisolone acetate, prednisolone sodium succinate,prednisolone butylacetate, prednisolone sodium phosphate, halopredoneacetate, methyl prednisolone, methyl prednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate,triamcinolone acetonide, dexamethasone, dexamethasone acetate,dexamethasone sodium phosphate, dexamethasone palmitate, paramethasoneacetate, and betamethasone etc.

Examples of the steroid preparation as an inhalant includebeclomethasone propionate, fluticasone propionate, budesonide,flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasonepalmitate, mometasone furoate, prasterone sulfate, deflazacort, methylprednisolone sreptanate, and methylprednisolone sodium succinate etc.

Examples of the β adrenoreceptor stimulant include, for example,fenoterol hydrobromide, salbutamol sulfate, terbutaline sulfate,formoterol fumarate, salmeterol xinafoate, isoproterenol sulfate,orciprenaline sulfate, clorprenaline sulfate, epinephrine, trimetoquinolhydrochloride, hexoprenaline sulfate, procaterol hydrochloride,tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride,clenbuterol hydrochloride, mabuterol hydrochloride, ritodrinehydrochloride, bambuterol, dopexamin hydrochloride, meluadrine tartrate,AR-C68397, levosalbutamol, R,R-formoterol, isoxsuprine, metaproterenol,KUR-1246, KUL-7211, AR-C89855, and S-1319 etc.

Examples of the leukotriene receptor antagonist include, for example,praniukast hydrate, montelukast, zafirlukast, seratrodast, MCC-847,KCA-757, CD-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178,S-36496, BIIL-284, and ONO-4057 etc.

Examples of the thromboxane synthesis enzyme inhibitor include, forexample, ozagrel hydrochloride, and imitrodast sodium etc.

Examples of the thromboxane A₂ receptor antagonist include, for example,seratrodast, ramatroban, domitroban calcium dihydrate, and KT-2-962 etc.

Examples of the mediator release inhibitor include, for example,tranilast, sodium cromoglicate, anlexanox, repirinast, ibudilast,tazanolast, and pemirolast potassium.

Examples of the antihistamines include ketotifen fumarate, mequitazine,azelastine hydrochloride, oxatomide, terfenadine, emedastine difumarate,epinastine hydrochloride, astemizole, ebastine, cetirizinehydrochloride, bepotastine, fexofenadine, loratadine, desloratadine,olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, mometasonefuroate, mizolastine, BP-294, andolast, auranofin, and acribastin etc.

Examples of the xanthine derivatives include, for example,aminophylline, theophylline, doxophylline, cipamphylline, anddiprophylline etc.

Examples of the anticholinergic preparation include, for example,ipratropium bromide, oxitropium bromide, flutropium bromide, cimetropiumbromide, temiverine, tiotropium bromide and revatropate (UK-112166) etc.

Examples of the cytokine inhibitor include, for example, suplatasttosilate (trade name: IPD) etc.

Examples of the expectorant include, for example, foeniculated ammoniaspirit, sodium hydrogen carbonate, bromhexine hydrochloride,carbocisteine, ambroxol hydrochloride, ambroxol hydrochloride sustainedrelease capsule, methylcysteine hydrochloride, acetyl cysteine, ethylL-cysteine hydrochloride and tyloxapol etc.

Examples of the growth factors include, for example, fibroblast growthfactor (FGF), vascular endothelial growth factor (VEGF), hepatocytegrowth factor (HGF) and insulin-like growth factor etc.

Examples of the nonsteroid-based antiphlogistic include, for example,sasapyrine, sodium salicylate, aspirin, aspirin dialuminate formulation,diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium,clinoril, fenbufen, napmetone, proglumetacin, indometacin farnesil,acemetacin, proglumetacin maleate, amfenac sodium, mofezolac, etodolac,ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofenaxetil, ketoprofen, fenoprofen calcium, tiaprofen, oxaprozin,pranoprofen, loxoprofen sodium, alminoprofen, zaltoprofen, mefenamicacid, aluminum mefenamate, tolfenamic acid, floctafenine,ketophenylbutazone, Oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam,napageln ointment, epirizole, tiaramide hydrochloride, tinoridinehydrochloride, emorfazone, sulpyrine, migrenin, saridon, sedes G,amipylo N, bisolvon, pyrine system antipyretics, acetaminophen,phenacetin, dimethothiazine mesylate, simetride formulation, antipyrinesystem antipyretics, bromfenac, fenamate, sulindac, nabumetone andketorolac etc.

Examples of the COX inhibitor include, for example, celecoxib, rofecoxiband etoricoxib etc.

Examples of the antispasmodic include, for example, scopolamine etc.

Examples of the Vasopressin V1a antagonist include, for example,relcovaptan etc.

Examples of the prostaglandin synthetase inhibitor include, for example,salazosulfapyridine, mesalazine, osalazine, 4-amino salicylic acid,JTE-522, auranofin, carprofen, diphenpyramide, flunoxaprofen,flurbiprofen, indometacin, Ketoprofen, lornoxicam, loxoprofen,meloxicam, oxaprozin, parsalmide, piproxen, piroxicam,piroxicam-β-cyclodextrin, piroxicam cinnamate, tropine indometacinate,zaltoprofen, pranoprofen, touki-syakuyaku-san and syakuyaku-kanzou-touetc.

Examples of the local anesthetic include, for example, cocainehydrochloride, procaine hydrochloride, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine, etidocaine,bupivacaine and 2-chloro butylcaine hydrochloride etc.

Examples of the calcium channel blocker include, for example,nifedipine, benidipine hydrochloride, diltiazem hydrochloride, verapamilhydrochloride, nisoldipine, nitrendipine, bepridil hydrochloride,amlodipine besilate, lomerizine hydrochloride, isradipine, nimodipine,felodipine and nicardipine etc.

Examples of the potassium channel blocker include, for example,dofetilide, E-4031, almokalant, sematilide, ambasilide, azimilide,tedisamil, RP5886, sotalol, piroxicam and ibutilide etc.

Examples of the vasodilator include, for example, nitroglycerin,isosorbide dinitrate and isosorbide mononitrate etc.

Examples of the diuretic include, for example, mannitol, furosemide,acetazolamide, diclofenamide, methazolamide, trichlormethazide,mefruside, spironolactone and aminophylline etc.

The weight proportion of the compound represented by formula (I) and theother pharmaceutical preparations is not specifically limited.

Arbitrary two or more of the other pharmaceutical preparations may beadministered in combination.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) include not only those which have so far beenfound but also those which will be found on the basis of theaforementioned mechanism.

In order to use the compound of the present invention represented byformula (I) or the compound represented by formula (I) in combinationwith the other pharmaceutical preparations, these compounds are normallyadministered to the entire or local part of human body orally orparenterally.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 ng to 100 mg, by oraladministration, up to several times per day, and from 0.1 ng to 10 mg,by parenteral administration, up to several times per day, or continuousadministration from 1 to 24 hours per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compound represented by formula (I) of the present invention, orconcomitant drug combined the compound represented by formula (I) withother drugs may be administered in the composition of, for example,solid compositions or liquid compositions, each for oral administration,or injections, external use, suppositories, eye drops or inhalat, eachfor parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders and granules. Capsules include hardcapsules and soft capsules.

In such solid forms, one or more of the active compound(s) may beadmixed with vehicles (such as lactose, mannitol, glucose,microcrystalline cellulose, starch), binders (such as hydroxypropylcellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate),disintegrants (such as cellulose calcium glycolate), lubricants (such asmagnesium stearate), stabilizing agents, and solution adjuvants (such asglutamic acid or aspartic acid) and prepared according to methods wellknown in normal pharmaceutical practice. The solid forms may, ifdesired, be coated with coating agents (such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), orbe coated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptablesolutions, suspensions and emulsions, syrups and elixirs. In such forms,one or more of the active compound(s) may be dissolved, suspended oremulsified into diluent(s) commonly used in the art (such as purifiedwater, ethanol or a mixture thereof). Besides such liquid forms may alsocomprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavoring agents, aroma,preservative or buffering agent.

In the parenteral administration, formulation of external use include,for example, ointment, gel, cream, poultice, patch, liniment, atomizedagent, inhalation, spray, aerosol, eye drops and nasal drops, etc. Theyincludes one or more of the active compound(s) and be prepared by knownmethod or usual method.

Ointment is prepared by known method or usual method. For example, it isprepared by levigation or fusion of one or more of the activecompound(s) and substrate. The substrate of ointment is selected fromknown or usual one. For example, higher fatty acid or higher fatty acidester (adipic acid, myristic acid, palmitic acid, stearic acid, oleicacid, adipic acid ester, myristic acid ester, palmitic acid ester,stearic acid ester, oleic acid ester, etc.), wax (yellow beeswax,Spermaceti, ceresin, etc.), surfactant (polyoxyethylene alkyl etherphosphoric acid ester, etc.), higher alcohol (cetanol, stearil alcohol,cetostearyl alcohol, etc.), silicon oil (dimethyl polysiloxane, etc.),hydrocarbon (hydrophilic petrolatum, white petrolatum, purified lanolin,light liquid paraffin, etc.), glycol (ethylene glycol, diethyleneglycol, propylene glycol, polyethylene glycol, macrogol, etc.),vegetable oil (castor oil, olive oil, sesame oil, turpentine oil, etc.),animal oil (mink oil, egg yolk oil, squalane, squalene, etc.), water,absorption accelerator, skin fit inhibitor, etc. are used as singlesubstance selected from them or mixture which consists of two or morekinds that is selected from them. Moreover, humectant, preservativeagent, stabilizer, antioxidative agent, fragrant materials, etc. may becontained.

Gel is prepared by known method or usual method. For example, it isprepared by fusion of one or more of the active compound(s) andsubstrate. The substrate of gel is selected from known or usual one. Forexample, lower alcohol (ethanol, isopropylalcohol, etc.), gelling agent(carboxy methyl cellulose, hydroxy ethyl cellulose, hydroxy propylcellulose, ethyl cellulose, etc.), neutralizing agent, (triethanolamine,diisopropanolamine, etc.), surfactant, (polyethylene glycolmonostearate, etc.), gum, water, absorption accelerator, skin fitinhibitor, etc. are used as single substance selected from them ormixture which consists of two or more kinds that is selected from them.Moreover, preservative agent, antioxidative agent, fragrant materials,etc. may be contained.

Cream is prepared by known method or usual method. For example, it isprepared by fusion or emulsification of one or more of the activecompound(s) and substrate. The substrate of cream is selected from knownor usual one. For example, higher fatty acid ester, lower alcohol,hydrocarbon, polyalcohol (propylene glycol, 1,3-butylene glycol, etc.),higher alcohol (2-hexyldecanol, cetanol, etc.), emulsifying agent(polyoxyethylene alkyl ether, fatty acid ester, etc.), water, absorptionaccelerator, skin fit inhibitor, etc. are used as single substanceselected from them or mixture which consists of two or more kinds thatis selected from them. Moreover, preservative agent, antioxidativeagent, fragrant materials, etc. may be contained.

Poultice is prepared by known method or usual method. For example, it isprepared by fusion of one or more of the active compound(s) andsubstrate, and then the kneaded one is laid over support medium. Thesubstrate for poultice is selected from known or usual one. For example,thickening agent (polyacrylic acid, polyvinylpyrolidone, gum acacia,starch, gelatin, methyl cellulose, etc.), bulking agent (kaolin, zincoxide, talc, calcium, magnesium, etc.), water, solubilizing agent,thickener, skin fit inhibitor, etc. are used as single substanceselected from them or mixture which consists of two or more kinds thatis selected from them. Moreover, preservative agent, antioxidativeagent, fragrant materials, etc. may be contained.

Patch is prepared by known method or usual method. For example, it isprepared by fusion of one or more of the active compound(s) andsubstrate, and then laid over support medium. The substrate for patch isselected from known or usual one. For example, polymer substrate, fat,higher fatty acid, thickener, skin fit inhibitor, etc. are used assingle substance selected from them or mixture which consists of two ormore kinds that is selected from them. Moreover, preservative agent,antioxidative agent, fragrant materials, etc. may be contained.

Liniment is prepared by known method or usual method. For example, oneor more of the active compound(s) may be dissolved, suspended oremulsified in water, alcohol (ethanol, polyethylene glycol, etc.),higher fatty acid, glycerin, soap, emulsifying agent, suspending agent,etc. as single substance selected from them or mixture which consists oftwo or more kinds that is selected from them. Moreover, preservativeagent, antioxidative agent, fragrant materials, etc. may be contained.

Atomized agent, inhalation and spray may comprise in addition to adiluent, a stabilizer such as sodium bisulfite and an isotonizationbuffer such as sodium chloride, sodium citrate or citric acid. Thepreparation process of sprays is described in detail in, for example,U.S. Pat. Nos. 2,868,691 and 3,095,355.

Injections for parenteral administration include sterile aqueous,suspensions, emulsions and solid forms which are dissolved or suspendedinto solvent(s) for injection immediately before use. In injections, oneor more of the active compound(s) may be dissolved, suspended oremulsified into solvent(s). The solvents may include distilled water forinjection, physiological salt solution, vegetable oil, propylene glycol,polyethylene glycol, alcohol, e.g., ethanol, or a mixture thereof.Injections may comprise some additives, such as stabilizing agents,solution adjuvants (such as glutamic acid, aspartic acid or Polysolvate80 (registered trade mark)), suspending agents, emulsifying agents,soothing agent, buffering agents, preservative. They may be sterilizedat a final step, or may be prepared by an aseptic manipulation . Theymay also be manufactured in the form of sterile solid forms, forexample, freeze-dried products, which may be dissolved in sterile wateror some other sterile diluent(s) for injection immediately before use.

The eye drops for parenteral administration may be in the form ofliquid, suspension, emulsion or ointment or may be dissolved in asolvent in use.

These eye drops are prepared by any known method. For example, one ormore active materials are dissolved, suspended or emulsified in asolvent. As such a solvent for eye drops there may be used sterilizedpurified water, physiological saline and other aqueous or nonaqueoussolvents (e.g., vegetable oil), singly or in combination. The eye dropsmay comprise an isotonic agent (e.g., sodium chloride, concentratedglycerin), a buffering agent (e.g., sodium phosphate, sodium acetate), asurface active agent (e.g., Polysolvate 80 (trade name), polyoxylstearate 40, polyoxyethylene-hardened castor oil), a stabilizer (sodiumcitrate, sodium edetate), a preservative (e.g., benzalconium chloride,Paraben), etc. properly selectively as necessary. The eye drops aresterilized at the final step or prepared by an aseptic manipulation.Alternatively, an aseptic solid agent such as freeze-dried product whichhas previously been prepared may be rendered aseptic or dissolved in anaseptic distilled water for injection or other solvent before use.

The dosage of inhalations for parenreral administration include aerosol,powders for inhalation or liquids for inhalation. The liquids forinhalation may be dissolved or suspended in water or the otherappropriate solvent as needed.

Such inhalations are prepared in a known method.

For example, a liquid for inhalation is prepared by selecting properadditives from an antiseptic (such as benzalkonium chloride orp-aminobenzonic acid), a coloring agent, a buffering agent (such assodium phosphate or sodium acetate), an isotonizing agent (such assodium chloride or concentrated glycerin), thickening agent (such ascarboxyvinylpolymer), or an accelerator of absorption, etc., ifnecessary.

A powder for inhalation is prepared by selecting proper additives from alubricant agent (such as stearin acid and the salt thereof), a bindingagent, (such as starch, dextrin), a diluting agent (such as lactose,cellulose), a coloring agent, an antiseptic (such as benzalkoniumchloride or p-aminobenzonic acid), an accelerator of absorption, etc.,if necessary.

In case of administration of liquid for inhalation, spray (atomizer,nebulizer) is usually used and in case of administration of powder forinhalation, inhalation administration apparatus for powder agents isusually used.

The other compositions for parenteral administration includesuppositories for intrarectal administration and pessaries for vaginaladministration which comprise one or more of the active substance(s) andmay be prepared by methods known per se.

Local Application:

Referring to the local administration of the invention, the compound ofthe present invention may be locally administered to site of disease(particularly bone diseases in which the amount of bone is decreased).The form of the compound of present invention is not limited to itsadministration method. the compound of present invention may be in theform of injection, solid agent such as embedding agent, pellet andpowder, and ointment to be administered to intramuscular, subcutaneousor articular site.

The extended-release preparation is not limited to its form so far asthe compound of the present invention can be continuously administeredto site of disease (particularly bone diseases in which the amount ofbone is decreased). The extended-release preparation may be in the formof, e.g., extended-release injection (e.g., microcapsuled preparation,microspheric preparation, nanospheric preparation), embeddingpreparation (e.g., film-like preparation) or the like.

The microcapsuled preparation, microspheric preparation and nanosphericpreparation of the present invention each are a finely dividedpharmaceutical composition with an in vivo degradable polymer comprisingas active components the compound represented by formula (I) optionallyin combination with other pharmaceutical preparations.

Examples of the in vivo degradable polymer of the present inventioninclude aliphatic acid ester polymers and copolymers thereof,polyacrylic acid esters, polyhydroxybutyric acids, polyalkyleneoxalates, polyorthoesters, polycarbonates, and polyaminoacids. Thesecompounds may be used singly or in admixture of two or more thereof.Examples of the aliphatic acid ester polymers and copolymers thereofinclude polylactic acid, polyglycolic acid, polycitric acid, polymalicacid, and lactic acid-glycolic acid copolymer. These compounds may beused singly or in admixture of two or more thereof. Besides thesecompounds, poly-α-cyanoacrylic acid esters, poly-p-hydroxybutyric acids,polytrimethyleneoxates, polyorthoesters, polyorthocarbonates,polyethylene carbonates, poly-y-benzyl-L-glutamic acids andpoly-L-alanines may be used singly or in admixture of two or morethereof. Among these compounds, preferred are polylactic acids,polyglycolic acids and lactic acid-glycolic acid copolymers, morepreferably lactic acid-glycolic acid copolymers.

The average molecular weight of these in vivo degradable polymers to beused in the present invention is preferably from about 2,000 to 800,000,more preferably from about 5,000 to 200,000. For example, the polylacticacid preferably has a weight-average molecular weight of from about5,000 to 100,000, more preferably from about 6,000 to 50,000. Thepolylactic acid can be synthesized according to any known preparationmethod per se. In the lactic acid-glycolic cid copolyrner, thecomposition ratio of the lactic acid to the glycolic acid is preferablyfrom about 100/0 to 50/50 (w/w), particularly from about 90/10 to 50/50.The weight-average molecular weight of the lactic acid-glycolic acidcopolymer is preferably from about 5,000 to 100,000, more preferablyfrom about 10,000 to 80,000. The lactic acid-glycolic acid copolymer canbe synthesized according to any known preparation method per se.

The term “weight-average molecular weight” as used herein is meant toindicate molecular weight in polystyrene equivalence determined by gelpermeation chromatography (GPC).

The aforementioned in vivo degradable polymer may be changed dependingon the intensity of pharmacological activity of the compoundsrepresented by formula (I) and the desired medicines to be released sofar as the aforementioned aims of the present invention areaccomplished. For example, the in vivo degradable polymer may be used inan amount of from about 0.2 to 10,000 times, preferably from about 1 to1,000 times, more preferably from about 1 to 100 times (by weight) thatof the physiologically active material.

Examples of the process for the preparation of microspheric,microcapsuled and nanospheric preparations include submerged dryingmethod (e.g., o/w method, w/o/w method), phase separation method, spraydrying method, granulation method by ulractritical fluid, and methodsanalogous thereto.

The submerged drying method (o/w method) and spray drying method will befurther described hereinafter.

-   (1) In the submerged drying method (o/w method), a solution of an in    vivo degradable polymer in an organic solvent is prepared at first.    The organic solvent to be used in the preparation of the    microspheric, microcapsuled and nanospheric preparations preferably    has a boiling point of 120° C. or less. Examples of the organic    solvent employable herein include halogenated hydrocarbons (e.g.,    dichloromethane, chloroform), aliphatic esters (e.g., ethyl    acetate), ethers, aromatic hydrocarbons, and ketones (e.g.,    acetone). These compounds may be used in admixture of two or more at    a proper ratio. Among these organic solvents, preferred are    dichloromethane and acetonitrile, particularly dichloromethane. The    concentration of the in vivo degradable polymer in the organic    solution depends on the molecular weight of the in vivo degradable    polymer, the kind of the organic solvent, etc. but is normally    predetermined to be from about 0.01 to 80% (v/w), preferably from    about 0.1 to 70% (v/w), more preferably from about 1 to 60% (v/w).

The compound represented by formula (I) is then added to and dissolvedin the solution of the in vivo degradable polymer in an organic solventthus obtained, optionally in combination with other pharmaceuticalpreparations. The amount of the compound represented by formula (I) tobe added optionally in combination with the other pharmaceuticalpreparations depends on the kind of the pharmaceutical preparations tobe added, the action of the pharmaceutical preparations in osteogenesis,the duration of the action, etc. but is normally from about 0.001% to90% (w/w), preferably from about 0.01% to 80% (w/w), more preferablyfrom about 0.3 to 30% (w/w) as calculated in terms of concentration inthe solution of in vivo degradable polymer in an organic solvent.

Subsequently, the organic solution thus prepared is added to an aqueousphase which is then processed by an agitator, emulsifier or the like toform an o/w emulsion. The volume of the aqueous phase during thisprocedure is predetermined to be from about 1 to 10,000 times,preferably from about 2 to 5,000 times, particularly from about 5 to2,000 times that of the oil phase. An emulsifier may be added to theaqueous phase which is an external phase. As such an emulsifier theremay be. normally used any material capable of forming a stable o/wemulsion. Examples of the emulsifier employable herein include anionicsurface active agents, nonionic surface active agents, polyoxyethylenecastor oil derivatives, polyvinyl pyrrolidone, polyvinyl alcohol,carboxymethyl cellulose, lecitine, and gelatin. These compounds may beused in proper combination. The concentration of the emulsifier in theexternal aqueous phase is preferably from about 0.001% to 20% (w/w),more preferably from about 0.01% to 10% (w/w), particularly from about0.05% to 5% (w/w).

The evaporation of the solvent which is an oil phase can be accomplishedby any commonly used method. In some detail, the evaporation of thesolvent may be effected at ordinary pressure or gradually fallingpressure with stirring by an agitator, magnetic stirrer or the like ormay be effected while the pressure is being adjusted using a rotaryevaporator. The microspheric preparation thus obtained is thenfractionated by centrifugal separation or filtration. The microsphericpreparation is washed with a surface active agent solution, alcohol orthe like several times to remove the free compound represented byformula (I), optionally in combination with other pharmaceuticalpreparations, and the emulsifier from the surface thereof, againdispersed in distilled water or a dispersant containing a vehicle (e.g.,mannitol, sorbitol, lactose), and then freeze-dried. In theaforementioned o/w method, the microspheric preparation may be preparedby a method involving the dispersion of the compound represented byformula (I) in a solvent of an in vivo degradable polymer in an organicsolvent, optionally in combination with other pharmaceuticalpreparations, i.e., s/o/w method.

-   (2) In order to prepare the microspheric preparation by the spray    drying method, an organic solvent or emulsion having the in vivo    degradable polymer and the compound represented by formula (I),    optionally in combination with other pharmaceutical preparations,    dissolved therein is sprayed into the drying chamber of a spray    dryer (spray dryer) through a nozzle so that the organic solvent or    water in the atomized droplets is evaporated in an extremely short    period of time to prepare a microspheric preparation. Examples of    the nozzle employable herein include two liquid nozzle, pressure    nozzle, and rotary disc. It is useful to spray an organic solvent or    an aqueous solution of an aggregation inhibitor (e.g., mannitol,    lactose, gelatin) at the same time with the spray of o/w emulsion as    necessary for the purpose of inhibiting the aggregation of    microspheres. The microspheric preparation thus obtained is then put    under reduced pressure optionally under heating to remove water and    solvent therefrom.

Examples of the film-like preparation include film-like materialobtained by dissolving the aforementioned in vivo degradable polymer andcompound represented by formula (I), optionally in combination withother pharmaceutical preparations, in an organic solvent, and thensubjecting the solution to evaporation to dryness and gelled materialobtained by dissolving the aforementioned in vivo degradable polymer andcompound represented by formula (I), optionally in combination withother pharmaceutical preparations, in a proper solvent, and then addinga granulating agent (e.g., cellulose, polycarbonate) to the solution.

The microsphere, microcapsule and nanosphere of the present inventionmay be used as they are. Alternatively, a spherical, rod-like, acicular,pelletized, film-like or cream-like pharmaceutical composition may beprocessed as a starting material to provide preparations in variousforms.

Furthermore, this preparation may be used as a parenteral for localadministration (e.g., injection, solid agent such as embedding agent,pellet and powder, liquid agent such as suspension, ointment, etc. to beadministered to intramuscular, subcutaneous, organic or articular site).For example, in order to make an injection from the microsphericpreparation, the microspheric preparation is suspended with adispersant, a preservative, an isotonic agent, a buffer, a pH adjustor,etc. to make an aqueous suspension as a practical preparation forinjection. Alternatively, the microspheric preparation may be dispersedwith a vegetable oil optionally in admixture with a phospholipid such aslecitine or with a middle-chain aliphatic acid triglyceride (e.g.,Mygliol-812) to make an oil suspension as an injection which can bepractically used.

The particle diameter of the microspheric preparation may be arbitraryso far as it suffices the desired dispersibility and passage throughsyringe if the preparation is used as a suspension for injection. By wayof example, the average particle diameter of the microsphericpreparation is from about 0.1 to 300 μm, preferably from about 1 to 150μm, more preferably from about 2 to 100 μm. The pharmaceuticalcomposition of the invention is preferably in the form of suspension asmentioned above. The pharmaceutical composition of the invention is alsopreferably in particulate form. This is because the pharmaceuticalcomposition gives less excessive pain to patients when administeredthrough a syringe for use in ordinary hypodermic or intramuscularinjection. It is particularly preferred that the pharmaceuticalcomposition of the invention be in the form of injection. Examples ofthe method for rendering the microspheric preparation aseptic includemethod which is aseptic throughout the entire steps, method involvingsterilization by gamma rays, and method involving the addition ofpreservative. However, the invention is not limited to these methods.

The pharmaceutical composition of the invention can be used for thetreatment of bone diseases in which the amount of bone is decreasedbecause the compound represented by formula (I), optionally incombination with other pharmaceutical preparations, can be graduallyreleased normally for 1 week to 3 months, though depending on the kindand added amount of the in vivo degradable polymer. Among these bonedisease treatments, the treatment of fracture often requires that theaffected part be fixed and covered with a plaster bandage and theadministration of pharmaceutical preparations be conducted only oncerather than frequently. Accordingly, the pharmaceutical preparationsthus administered are required to accelerate treatment continuously.Thus, the pharmaceutical composition of the invention is usefulparticularly in this treatment.

The dose of the pharmaceutical composition of the present inventiondepends on the kind, content and form of the compound represented byformula (I), optionally in combination with other pharmaceuticalpreparations, the duration of release of pharmaceutical preparations,the animal to be administered, etc., but may be the effective amount ofthe compound represented by formula (I), optionally in combination withother pharmaceutical preparations. When administered to fracture as amicrospheric preparation, for example, one time dose for adult (weight:50 kg) is from about 0.001 mg to 500 mg, preferably from about 0.01 mgto 50 mg as calculated in terms of effective component. Thepharmaceutical composition of the invention may be administered once 1week to 3 months in the aforementioned amount.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained below in detail based on ReferenceExamples and Examples, however, the present invention is not limitedthereto.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC.

The solvents in the parentheses in NMR show the solvents formeasurement.

HPLC was carried out in measurement condition F.

THP is tetrahydropyran-2-yl and Boc is t-butoxycalbonyl.

When a compound includes two diastereomers, “more polar” represents acompound having less Rf value, and “less polar” represents a compoundhaving more Rf value.

Name of the compounds in Example 1 to 10 were named according to IUPACnomenclature system or popular name nomenclature system. Name of thecompounds in Example 11 to 22 were named using ACD/Name Pro ver. 6.0 oraccording to IUPAC nomenclature system or popular name nomenclaturesystem.

REFERENCE EXAMPLE 1 S-(2,2-diethoxyethyl)ethanethioate

Under an atmosphere of argon, 2-bromoacetaldehyde diethyl acetal (7.29g) and potassium thioacetate (4.23 g) were mixed in dimethylformamide(20 mL) and the mixture was stirred at 50° C. for 5 hours. Aftercooling, water was added to the reaction solution, which was extractedby ethyl acetate-hexane mixed solvent. The organic layer was washed withwater and brine, dried over anhydrous magnesium sulfate and concentratedto give the title compound (7.10 g) having the following physical data.

TLC: Rf 0.56 (n-hexane:ethyl acetate=9:1);

NMR (CDCl₃): δ 4.43 (t, J=5.4 Hz, 1H), 3.67-3.43 (m, 4H), 3.04 (d, J=5.4Hz, 2H), 2.28 (s, 3H), 1.14 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 2 2-(2,2-diethoxyethylthio)thiazole-4-carboxylic acidethyl ester

To a solution of the compound prepared in Reference Example 1 (1.76 g),2-bromothiazole-4-carboxylic acid ethyl ester (1.80 g) andtributylphosphine (0.19 mL) in ethanol (10 mL) was added potassiumcarbonate (1.57 g) in ice bath and the mixture was stirred at roomtemperature ovemight. Water was added to the reaction solution, whichwas extracted with ethyl acetate. The organic layer was washed withwater and brine, dried over anhydrous magnesium sulfate and concentratedto give the title compound. The obtained compound was used in nextreaction without purification.

TLC: Rf 0.40 (toluene:ethyl acetate=9:1);

NMR (CDCl₃): δ 8.02 (s, 1H), 4.77 (t, J=5.4 Hz, 1H), 4.39 (q, J=7.2 Hz,2H), 3.79-3.54 (m, 4H), 3.47 (d, J=5.4 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H),1.22 (t, J=7.2 Hz, 6H).

REFERENCE EXAMPLE 3 2-(formylmethylthio)thiazole-4-carboxylic acid ethylester

The compound prepared in Reference Example 2 was dissolved in ethanol(15 mL) and 2N hydrochloric acid (5.7 mL) was added thereto. The mixturewas stirred at 60° C. for 3 hours. After cooling, water was added to thereaction solution, which was extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=3:1) to give thetitle compound (714 mg) having the following physical data.

TLC: Rf 0.20 (n-hexane:ethyl acetate=4:1);

NMR (CDCb₃): δ 9.72 (t, J=2.1 Hz, 1H), 8.05 (s, 1H), 4.39 (q, J=6.9 Hz,2H), 4.09 (d, J=2.1 Hz, 2H), 1.39 (t, J=6.9 Hz, 3H).

REFERENCE EXAMPLE 4 (1S)-1-(1-ethylcyclobutyl)-3-(1-phenyl-1H-tetrazol-5-ylthio)propan-1-ol

To a solution of (1S)-1-(1-ethylcyclobutyl)-propane-1,3-diol (8.90 g) intoluene (110 mL) were added tetrabutylammonium chloride (1.56 g) and a2N aqueous sodium hydroxide solution (170 mL). At an inner temperatureabout 25° C., tosyl chloride (11.3 g) was added to the reactionsolution, which was stirred at 25° C. for 1 hour.1-Phenyl-1H-tetrazol-5-thiol (11.0 g) was added to the reactionsolution, which was stirred at 60° C. for 1 hour. After cooling, waterwas added to the reaction solution, which was separated. The water layerwas extracted with t-butyl methyl ether. The mixed organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate andconcentrated to give the title compound (17.9 g) having the followingphysical data.

TLC: Rf 0.67 (n-hexane:ethyl acetate=1:1).

REFERENCE EXAMPLE 5(1S)-1-(1-ethylcyclobutyl)-3-(1-phenyl-1H-tetrazol-5-ylsulfonyl)propan-1-ol

To a solution of the compound prepared in Reference Example 4 (17.9 g)in methanol (225 mL) was added a solution of potassium peroxymonosulfate(OXONE:brand name) (52.0 g) in water (225 mL) at room temperature andthe mixture was stirred at 60° C. for 8 hours. After cooling, water wasadded to the reaction solution, which was extracted with ethyl acetate.The organic layer was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated to give the title compound (19.7 g)having the following physical data. TLC:Rf 0.78 (n-hexane:ethylacetate=1:1).

REFERENCE EXAMPLE 6(1S)-1-(1-ethylcyclobutyl)-3-(1-phenyl-1H-tetrazol-5-ylsulfonyl)-1-(tetrahydropyran-2-yloxy)propane

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 5 (19.7 g) and 2,3-dihydro-2H-pyran (5.68 g) inmethylene chloride (100 mL) was added p-toluenesulfonic acid monohydrate(54 mg) in ice bath and the mixture was stirred at 0° C. to 10° C. for 2hours. Triethylamine (1 mL) was added to the reaction solution, whichwas concentrated. The obtained residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=9:1→4:1) to givethe title compound (15.3 g) having the following physical data.

TLC: Rf 0.50 and 0.45 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃) δ 7.80-7.50 (m, 5H), 4.65 (m, 0.3H), 4.44 (m, 0.7H),4.05-3.40 (m, 5H), 2.30-1.35 (m, 16H), 1.00-0.85 (m, 3H).

REFERENCE EXAMPLE 7 (4R)-4-formyl-4-t-butoxycarbonylaminobutanoic acidethyl ester

Under an atmosphere of argon, to a mixed solution of(4R)-4-t-butoxycarbonylamino-5-hydroxypentanoic acid ethyl ester (1.62g) and diisopropylethylamine (6.5 ml) in dimethylsulfoxide-ethyl acetate(1:1, 40 mL) was added sulfur trioxide pyridine complex (2.96 g) in icebath and the mixture was stirred in ice bath for 1 hour. The reactionsolution was poured into ice water and extracted with ethyl acetate. Theorganic layer was washed with 0.5N hydrochloric acid, water and brine,dried over anhydrous magnesium sulfate and concentrated to give thetitle compound (1.65 g) having the following physical data.

TLC: Rf 0.25 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 9.60 (s, 1H), 5.20 (br, 1H), 4.27 (br, 1H), 4.14 (q,J=7.2 Hz, 2H), 2.60-2.20 (m, 3H), 1.91 (m,1 H), 1.45 (s, 9H), 1.26 (t,J=7.2 Hz, 3H).

REFERENCE EXAMPLE 8 (4R,5E,8S)-4-t-butoxycarbonylamino-8-(1-ethylcyclobutyl)-8-(tetrahydropyran-2-yloxy)oct-5-enoicacid ethyl ester

Under an atmosphere of argon, a solution of 0.5M potassiumbis(trimethylsilyl)amide in toluene (18.6 ml) was added dropwise to asolution of the compound prepared in Reference Example 6 (4.31 9) inanhydrous 1,2-dimethoxyethane (30 ml) at −78° C. and the mixture wasstirred for 1 hour at the same temperature. A solution of the compoundprepared in Reference Example 7 (1.65 g) in 1,2-dimethoxyethane (10 ml)was added dropwise to the reaction mixture, which was allowed to returnto 0C for 2 hours. A saturated aqueous sodium hydrogen carbonatesolution was added to the reaction solution, which was extracted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas purified by column chromatography on silica gel (n-hexane:ethylacetate=9:1→4:1) to give the title compound (1.20 g) having thefollowing physical data.

TLC: Rf 0.50 (n-hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 5.85-5.55 (m, 1H), 5.45-5.30 (m, 1H), 4.65-4.55 (m, 1H),4.20-3.85 (m, 5H), 3.65-3.40 (m, 2H), 2.45-1.40 (m, 20H), 1.43 (s, 9H),1.30-1.20 (m, 3H), 1.00-0.85 (m, 3H).

REFERENCE EXAMPLE 9(4R,5E,8S)-4-amino-8-(1-ethylcyclobutyl)-8-hydroxyoct-5-enoic acid ethylester hydrochloride

To a solution of the compound prepared in Reference Example 8 (172 mg)in ethanol (2 ml) was added 4N hydrogen chloride dioxane solution (0.5ml) was the mixture was stirred at room temperature for 8 hours. Thereaction solution was concentrated to give the title compound (120 mg).

TLC: Rf 0.20(chloroform:methanol=9:1).

EXAMPLE 1(13E,16α)-17,17-propano-16-hydroxy-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

Under an atmosphere of argon, a solution of the compound prepared inReference Example 9 (120 mg) and the compound prepared in ReferenceExample 3 (102 mg) in tetrahydrofuran (2 mL) was stirred at roomtemperature for 30 minutes. To the solution was added sodiumtriacetoxyborohydride (116 mg) and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, whichwas extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was purified by column chromatography on silica gel(ethyl acetate) to give the compound of the present invention (93 mg)having the following physical data.

TLC: Rf 0.29 (ethyl acetate);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.82 (dt, J=15.3, 6.9 Hz, 1H), 5.39 (dd,J=15.3, 8.7 Hz 1H), 4.39 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 3.82 (m, 1H),3.56-3.35 (m, 4H), 2.50-1.55 (m, 13H), 1.40 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.26 (m, 1H), 0.90 (t, J=7.5 Hz 3H).

EXAMPLE 1(1) TO 1 (16)

By the same procedure as described in Example 1, using the compoundprepared in Reference Example 3 or a corresponding aldehyde derivative,and the compound prepared in Reference Example 9 or a correspondingamine derivative, the following compounds of the present invention wereobtained.

EXAMPLE 1(1)(13E)-20-methyl-15-hydroxy-9-oxo-5,17-dithia-8-azaprost-13-enoic acidbutyl ester

more polar

TLC: Rf 0.40 (ethyl acetate);

NMR (CDCl₃): δ 5.73 (dd, J=15.3, 5.1 Hz, 1H), 5.61 (dd, J=15.3, 8.1 Hz,1H), 4.24 (m, 1H), 4.15 (m, 1H), 4.08 (t, J=7.2 Hz, 2H), 3.68 (m, 1H),3.11 (m, 1H), 2.80-2.20 (m, 13H), 1.97-1.70 (m, 3H), 1.67-1.32 (m, 8H),0.94 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H).

The compound is a single isomer although the configuration at15-position is not determined.

EXAMPLE 1(2)(13E,15α)-15-hydroxy-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.51 (ethyl acetate);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.78 (dd, J=15.3, 5.7 Hz, 1H), 5.54 (dd,J=15.3, 9.0 Hz, 1H), 4.39 (q, J=6.9 Hz, 2H), 4.21 (m, 1H), 4.10 (m, 1H),3.79 (m, 1H), 3.50-3.38 (m, 3H), 2.50-2.10 (m, 3H), 1.95 (bs, 1H), 1.77(m, 1H), 1.66-1.20 (m, 11H), 0.87 (t, J=6.9 Hz, 3H).

EXAMPLE 1(3) (13E,15α)-20,20-ethano-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic acid butylester

TLC: Rf 0.49 (ethyl acetate);

NMR (CDCl₃): δ 5.74 (dd, J=15.9, 6.0 Hz, 1H), 5.52 (dd, J=15.9, 8.4 Hz,1H), 4.21-4.03 (m, 4H), 3.63 (m, 1H), 3.10 (m, 1H), 2.73-2.20 (m, 9H),1.98-1.18 (m, 16H), 0.93 (t, J=7.5 Hz, 3H), 0.65 (m, 1H), 0.40 (m, 2H),0.00 (m, 2H).

EXAMPLE 1(4) (13E,16α)-17,17-propano-16-hydroxy-9-oxo-20-nor-8-azaprost-13-enoic acidethyl ester

TLC: Rf 0.42 (ethyl acetate);

NMR (CDCl₃): δ 5.77 (dt, J=15.3, 7.2 Hz, 1H), 5.38 (dd, J=15.3, 9.0 Hz,1H), 4.12 (q, J=7.2 Hz, 2H), 4.03 (m, 1H), 3.62-3.44 (m, 2H), 2.88 (m,1H), 2.50-1.20 (m, 23H), 2.28 (t, J=7.5 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H),0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 1(5) (13E,16α)-17,17-propano-16-hydroxy-9-oxo-2,7-(1,3-interphenylene)-3,4,5,6,20-pentanor-8-azaprost-13-enoicacid methyl ester

TLC: Rf 0.54 (chloroform:methanol=9:1);

NMR (CDCl₃): 7.30-7.22 (m, 1H), 7.20-7.10 (m, 3H), 5.70 (dt, J=15.0, 7.2Hz, 1H), 5.34 (dd, J=15.0, 9.0 Hz, 1H), 4.91 (d, J=15.0 Hz, 1H), 3.92(d, J=15.0 Hz, 1H), 3.87 (m, 1H), 3.70 (s, 3H), 3.61 (s, 2H), 3.52 (dd,J=9.9, 2.1 Hz, 1H), 2.55-1.35 (m, 14H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 1(6)(13E,16α)-17,17-propano-16-hydroxy-9-oxo-1,5-(1,3-interphenylene)-2,3,4,20-tetranor-8-azaprost-13-enoicacid ethyl ester

TLC: Rf 0.38(ethyl acetate);

NMR (CDCl₃): δ 7.86 (m, 2H), 7.36 (m, 2H), 5.72 (m, 1H), 5.35 (dd,J=15.3, 8.7 Hz, 1H), 4.37 (q, J=6.9 Hz, 2H), 4.00 (m, 1H), 3.63-3.45 (m,2H), 2.98 (m, 1H), 2.65 (m, 2H), 2.50-2.07 (m, 4H), 2.05-1.23 (m, 16H),0.91 (t, J=7.5 Hz, 3H).

EXAMPLE 1(7)(13E,16α)-17,17-propano-16-hydroxy-9-oxo-1,5-(2,5-interthienylene)-2,3,4,20-tetranor-8-azaprost-13-enoicacid methyl ester

TLC: Rf 0.32 (ethyl acetate);

NMR (CDCl₃): δ 7.61 (d, J=3.6 Hz, 1H), 6.80 (d, J=3.6 Hz, 1H), 5.75 (m,1H), 5.36 (dd, J=15.0, 8.7 Hz, 1H), 4.01 (m, 1H), 3.86 (s, 3H), 3.66 (m,2H), 3.03 (m, 1H), 2.82 (m, 2H), 2.50-2.15 (m, 4H), 2.10-1.37 (m, 13H),0.90 (t, J=7.5 Hz, 3H).

EXAMPLE 1(8)(13E,16α)-17,17-propano-16-hydroxy-9-oxo-1,6-(1,4-interphenylene)-2,3,4,5,20-pentanor-8-azaprost-13-enoicacid methyl ester

TLC: Rf 0.27 (ethyl acetate).

EXAMPLE 1(9)(13E)-17,17-propano-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.29 (n-hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.68 (dt, J=15.3, 6.6 Hz, 1H), 5.22 (dd,J=15.3, 9.0 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 4.13 (m, 1H), 3.83 (m, 1H),3.49-3.41 (m, 2H), 3.32 (m, 1H), 2.44-2.29 (m, 2H), 2.19 (m, 1H),2.04-1.48 (m, 8H), 1.43-1.31 (m, 6H), 1.05 (s, 3H).

EXAMPLE 1(10)(16α)-17,17-propano-16-hydroxy-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprostane

TLC: Rf 0.25 (ethyl acetate);

NMR (CDCl₃): δ 8.01 (s, 1H), 4.38 (q, J=7.2 Hz, 2H), 3.89 (m, 1H), 3.72(m, 1H), 3.56-3.30 (m, 4H), 2.46-2.09 (m, 3H), 2.02-1.20 (m, 16H), 1.39(t, J=7.2 Hz, 3H), 0.91 (t, J=7.5 Hz, 3H).

EXAMPLE 1(11)

(13E,16α)-17,17-propano-16-hydroxy-9-oxo-1,5-(1,4-interphenylene)-2,3,4,20-tetranor-8-azaprost-13-enoicacid methyl ester

TLC: Rf 0.29 (ethyl acetate);

NMR (CDCl₃): δ 7.95 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 5.69 (dt,J=15.3, 6.9 Hz, 1H), 5.34 (dd, J=15.3, 8.7 Hz, 1H), 3.97 (m, 1H), 3.90(s, 3H), 3.72-3.45 (m, 2H), 2.97 (m, 1H), 2.66 (t, J=7.8 Hz, 2H),2.50-1.55 (m, 15H), 1.50-1.35 (m, 2H), 0.91 (t, J=7.5 Hz, 3H).

EXAMPLE 1(12)

(13E,16α)-17,17-propano-16-hydroxy-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-8-azaprost-13-ene

TLC: Rf 0.14 (ethyl acetate);

NMR (CDCl₃): δ 8.04 (s, 1H), 5.78 (dt, J=15.3, 6.6 Hz, 1H), 5.38 (dd,J=15.3, 8.7 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.06 (m, 1H), 3.65-3.50 (m,2H), 3.10-3.00 (m, 2H), 2.50-1.55 (m, 17H), 1.43 (m, 1H), 1.40 (t, J=7.2Hz, 3H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 1(13)

(13E,16α)-17,17-propano-16-hydroxy-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5,8-diazaprost-13-ene

TLC: Rf 0.49 (ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ 7.37 (s, 1H), 6.07 (br, 1H), 5.81 (dt, J=15.3, 6.6 Hz,1H), 5.41 (dd, J=15.3, 9.0 Hz, 1H), 4.34 (q, J=6.9 Hz, 2H), 4.07 (m,1H), 3.66-3.40 (m, 5H, 2.50-1.60 (m, 14H), 1.44 (m, 1 H), 1.36 (t, J=6.9Hz, 3H), 0.92 (t, J=7.5 Hz, 3H).

EXAMPLE 1(14)

(13E)-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.30 (hexane:ethyl acetate=1:2);

NMR δ 8.02 (s, 1H), 5.66 (dt, J=15.3, 6.9 Hz, 1H), 5.21 (dd, J=15.3, 8.7Hz, 1H), 4.39 (q, J=6.9 Hz, 2H), 4.14 (m, 1H), 3.83 (dt, J=13.5, 6.9 Hz,1H), 3.48-3.40 (m, 2H), 3.30 (dt, J=13.5, 6.9 Hz, 1H), 2.48-2.10 (m,4H), 2.08-1.93 (m, 2H), 1.71 (m, 1H), 1.39 (t, J=6.9 Hz, 3H), 1.35-1.16(m, 5H), 0.86 (t, J=7.2 Hz, 3H).

EXAMPLE 1(15)(13E)-17,17-propano-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.32 (hexane:ethyl acetate=1:2);

NMR(CDCl₃): δ 8.02 (s, 1H), 5.69 (dt, J=15.3, 6.6 Hz, 1H), 5.21 (dd,J=15.3, 9.0 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 4.12 (m, 1H), 3.84 (dt,J=13.5, 6.9 Hz, 1H), 3.50-3.39 (m, 2H), 3.31 (dt, J=13.5, 6.9 Hz, 1H),2.48-2.12 (m, 3H), 1.96-1.52 (m, 8H), 1.47-1.32 (m, 8H), 0.74 (t, J=7.2Hz, 3H).

EXAMPLE 1(16)(13E)-14-(3,5-dichlorophenyl)-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.27 (hexane:ethyl acetate=1:2);

NMR(CDCl₃): δ 7.95 (s, 1H), 7.23 (t, J=1.8 Hz, 1H), 7.18 (d, J=1.8 Hz,2H), 6.50 (d, J=15.9, 1H), 6.04 (dd, J=15.9, 9.0 Hz, 1H), 4.47-4.34 (m,3H), 3.89 (m, 1H), 3.56-3.28 (m, 3H), 2.55-2.14 (m, 3H), 1.8 6 (m, 1H),1.38 (t, J=7.2 Hz, 3H).

EXAMPLE 2

(13E,16)-17,17-propano-16-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

To a solution of the compound prepared in Example 1 (93 mg) in ethanol(2 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL) and themixture was stirred at room temperature for 2 hours. The reactionsolution was neutralized with hydrochloric acid and then extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue waspurified by column chromatography on silica gel(chloroform:methanol:acetic acid=90:10:1) to give the compound of thepresent invention (78 mg) having the following physical data.

TLC: Rf 0.25 (chloroform:methanol=4:1);

NMR (CDCl₃): δ 8.08 (brs, 1H), 5.84 (m, 1H), 5.40 (m, 1H), 4.10 (m, 1H),4.00-2.50 (br, 2H), 3.78 (m, 1H), 3.59 (m, 1H), 3.49 (m, 1H), 3.32 (m,2H), 2.50-1.58 (m, 12H), 1.44 (m, 1H), 1.26 (m, 1H), 0.92 (t, J=7.5 Hz,3H).

EXAMPLES 2(1) TO 2(16)

By the same procedure as described in Example 2, using the compoundprepared in Example 1(1) to 1(16) instead of the compound prepared inExample 1, the following compounds of the present invention wereobtained.

EXAMPLE 2(1)(13E)-20-methyl-15-hydroxy-9-oxo-5,17-dithia-8-azaprost-13-enoic acid

more polar

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 5.75 (dd, J=15.6, 4.8 Hz, 1H), 5.63 (dd, J=15.6, 8.1 Hz,1H), 4.25 (m, 1H), 4.17 (m, 1H), 3.66 (m, 1H), 3.23-2.20 (m, 16H),1.99-1.70 (m, 3H), 1.58 (m, 2H), 1.40 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).

The compound is a single isomer although the configuration at15-position is not determined.

EXAMPLE 2(2)(15α,13E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.30 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.10 (s, 1H), 5.80 (dd, J=15.6, 6.0 Hz, 1H), 5.55 (dd,J=15.6, 8.7 Hz, 1H), 4.30-3.77 (m, 5H), 3.60-3.29 (m, 3H), 2.58-2.20 (m,3H), 1.80 (m, 1H), 1.62-1.21 (m, 8H), 0.88 (t, J=7.5 Hz, 3H).

EXAMPLE 2(3)(15α,13E)-20,20-ethano-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic acid

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 5.73 (dd, J=15.3, 5.7 Hz, 1H), 5.53 (ddd, J=15.3, 8.1,1.0 Hz, 1H), 4.18 (m, 2H), 3.63 (m, 1H), 3.30-2.78 (m, 2H), 2.75-2.20(m, 10H), 1.98-1.67 (m, 3H), 1.62-1.10 (m, 8H), 0.62 (m, 1H), 0.40 (m,2H), -0.02 (m, 2H).

EXAMPLE 2(4)(13E,16α)-17,17-propano-16-hydroxy-9-oxo-20-nor-8-azaprost-13-enoic acid

TLC: Rf 0.38 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 5.79 (dt, J=15.3, 6.9 Hz, 1H), 5.38 (dd, J=15.3, 8.7 Hz,1H), 4.05 (m, 1H), 4.00-3.00 (br, 2H), 3.58 (dd, J=9.9,2.4 Hz,1H), 3.52(m, 1H), 2.87 (m, 1H), 2.50-1.20 (m, 24H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 2(5)(13E,16at)-17,17-propano-16-hydroxy-9-oxo-2,7-(1,3-interphenylene)-3,4,5,6,20-pentanor-8-azaprost-13-enoicacid

TLC: Rf 0.32 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.25 (m, 1H), 7.20-7.10 (m, 3H), 5.71 (dt, J=15.3, 7.2Hz, 1H), 5.32 (dd, J=15.3, 9.0 Hz, 1H), 4.96 (d, J=14.4 Hz, 1H),4.50-3.00 (br, 2H), 3.86 (d, J=14.4 Hz, 1H), 3.81 (m, 1H), 3.65 (d,J=15.3 Hz, 1H), 3.59 (d, J=15.3 Hz, 1H), 3.56 (dd, J=9.9, 2.1 Hz, 1H),2.55-1.50 (m, 13H), 1.44 (m, 1H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 2(6)(13E,16α)-17,17-propano-16-hydroxy-9-oxo-1,5-(1,3-interphenylene)-2,3,4,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.93 (m, 2H), 7.45-7.38 (m, 2H), 5.74 (m, 1H), 5.36 (dd,J=15.3, 9.0 Hz, 1H), 4.01 (m, 1H), 3.63-3.51 (m, 2H), 3.00 (m, 1H), 2.67(t, J=7.0 Hz, 2H), 2.55-2.12 (m, 4H), 2.08-1.58 (m, 12H), 1,41 (m, 1H),0.91 (t, J=7.8 Hz, 3H).

EXAMPLE 2(7)(13E,16α)-17,17-propano-16-hydroxy-9-oxo-1,5-(2,5-interthienylene)-2,3,4,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.19 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.68 (d, J=3.9 Hz, 1H), 6.83 (d, J=3.9 Hz, 1H), 5.77 (m,1H), 5.65 (bs, 1H), 5.36 (dd, J=15.3, 8.7 Hz, 1H), 4.05 (m, 1H),3.62-3.50 (m, 2H), 3.03 (m, 1H), 2.86 (t, J=7.0 Hz, 2H), 2.55-2.18 (m,4H), 2.11-1.58 (m, 12H), 1.41 (m, 1H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 2(8)(13E,16α)-17,17-propano-16-hydroxy-9-oxo-1,6-(1,4-interphenylene)-2,3,4,5,20-pentanor-8-azaprost-13-enoicacid

TLC: Rf 0.28 (ethyl acetate:acetic acid=100:1);

NMR (CDCl₃): δ 8.01 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 5.67(ddd, J=15.3, 8.1, 6.6 Hz, 1H), 5.27 (dd, J=15.3, 9.0 Hz, 1H), 3.88-3.72(m, 2H), 3.57 (dd, J=9.6, 2.7 Hz, 1H), 3.20 (m, 1H), 3.00-2.80 (m, 2H),2.50-1.58 (m, 13H), 1.45 (m, 1H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 2(9)(13E)-17,17-propano-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.35 (chloroform:methanol:acetic acid=9: 1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 5.74 (dt, J=15.0, 6.9 Hz, 1H), 5.27 (dd,J=15.0, 8.4 Hz, 1H), 4.06 (m, 1H), 3.82 (m, 1H), 3.49 (m, 1H), 3.40-3.20(m, 2H), 2.53-2.15 (m, 3H), 2.09-1.53 (m, 9H), 1.50-1.40 (m, 2H),1.08(s, 3H).

EXAMPLE 2(10)(16α)-17,17-propano-16-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprostane

TLC: Rf 0.28 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 8.07 (s, 1H), 5.00-4.00 (br, 2H), 3.88 (m, 1H), 3.75-3.20(m, 5H), 2.50-1.20 (m, 18H), 0.91 (t, J=7.2 Hz, 3H).

EXAMPLE 2(11)(13E,16α)-17,17-propano-16-hydroxy-9-oxo-1,5-(1,4-interphenylene)-2,3,4,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.24 (ethyl acetate:acetic acid=100:1);

NMR (CDCl₃): δ 8.00 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.00-4.00(br, 2H), 5.71 (dt, J=15.6, 6.9 Hz, 1H), 5.36 (dd, J=15.6, 8.7 Hz, 1H),4.00 (m, 1H), 3.58 (m, 1H), 3.53 (dd, J=9.9,2.4 Hz, 1H), 2.98 (m, 1H),2.67 (t, J=7.5 Hz, 2H), 2.50-1.55 (m, 15H), 1.43 (m, 1H), 0.91 (t, J=7.2Hz, 3H).

EXAMPLE 2(12)(13E,16α)-17,17-propano-16-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-8-azaprost-13-ene

TLC: Rf 0.47 (chloroform:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 8.13 (s, 1H), 5.81 (dt, J=15.0, 7.2 Hz, 1H), 5.41 (dd,J=15.0, 8.7 Hz, 1H), 5.50-4.00 (br, 2H), 4.07 (m, 1H), 3.61 (dd, J=9.6,2.7 Hz, 1H), 3.56 (m, 1H), 3.14 (m, 1H), 3.04 (t, J=7.5 Hz, 2 H),2.50-1.60 (m, 15H), 1.45 (m, 1H), 0.92 (t, J=7.5 Hz, 3H).

EXAMPLE 2(13)(13E,16α)-17,17-propano-16-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5,8-diazaprost-13-ene

TLC: Rf 0.49 (chloroform:methanol:acetic acid=80:20:1);

NMR (CDCl₃):δ 11.78 (br, 1H), 7.31 (s, 1H), 6.03 (dt, J=15.0, 7.2 Hz,1H), 5.29 (dd, J=15.0, 8.7 Hz, 1H), 4.07 (m, 1H), 3.65-3.30 (m, 5H),2.50-1.55 (m, 15H), 1.42 (m, 1H), 0.90 (t, J=7.5 Hz, 3H).

EXAMPLE 2(14)(13E)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.37 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 5.72 (dt, J=15.3, 6.6 Hz, 1H), 5.27 (dd,J=15.3, 9.0 Hz, 1H), 4.05 (m, 1H), 3.80 (m, 1H), 3.51 (m, 1H), 3.40-3.21(m, 2H), 2.54-2.15 (m, 3H), 2.13-2.00 (m, 2H), 1.75 (m, 1H), 1.4 5-1.17(m, 6H), 0.89 (t, J=6.6 Hz, 3H).

EXAMPLE 2(15)(13E)-17,17-propano-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.37 (chloroform:methanol:acetic acid=9: 1:0.1);

NMR(CDCl₃): δ 8.09 (s, 1H), 5.74 (dt, J=15.3, 6.6 Hz, 1H), 5.28 (dd,J=15.3, 8.7 Hz, 1H), 4.06 (m, 1H), 3.82 (m, 1H), 3.49 (m, 1H), 3.41-3.23(m, 2H), 2.54-2.16 (m, 3H), 2.04-1.89 (m, 2H), 1.88-1.63 (m, 7H),1.52-1.40 (m, 4H), 0.77 (t, J=7.2 Hz, 3H).

EXAMPLE 2(16)(13E)-14-(3,5-dichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.33 (chloroform:methanol:acetic acid=9:1:0.1);

NMR(CDCl₃): δ 8.08 (s, 1H), 7.27 (t, J=1.8 Hz, 1H), 7.24 (d, J=1.8 Hz,2H), 6.49 (d, J=15.6, 1H), 6.07 (dd, J=15.6, 8.7 Hz, 1H), 4.30 (m, 1H),3.90 (m, 1H), 3.49 (m 3.41-3.30 (m, 2H), 2.62-2.43 (m, 2H), 2.35 (m,1H),1.89 (m,1H).

REFERENCE EXAMPLE 10 2-(2-aminoethylthio)thiazole-4-carboxylic acidethyl ester hydrochloride

To a solution of 2-bromothiazole-4-carboxylic acid ethyl ester (3.00 g)in ethanol (15 mL) were added tributylphosphine (25 mg) and cysteamine(1.2 g) and the mixture was stirred at room temperature for 16 hours.Furthermore, cysteamine (1.0 g) was added thereto and the mixture wasstirred at 50° C. for 5 hours. After cooling to room temperature, thereaction solution was neutralized with an aqueous saturated sodiumhydrogen carbonate solution and extracted with chloroform. The organiclayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated. The residue was diluted with ethyl acetate (30 mL) and 4Nhydrogen chloride-ethyl acetate solution was added thereto. Theprecipitated solid was collected by filtration to give the titlecompound (2.28 g) having the following physical data.

TLC: Rf 0.20 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 8.33 (s, 1H), 4.37 (q, J=7.2 Hz, 2H), 3.55 (t, J=6.6 Hz,2H), 3.37 (t, J=6.6 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 11 3-(4-t-butylbenzoyl)propanoic acid ethyl ester

To a solution of t-butylbenzene (2.00 g) in 1,2-dichloroethane (30 mL)was added aluminum chloride (2.2 g) in ice bath. Ethyl succinyl chloride(2.3 mL) was added dropwise to the mixture, which was stirred at roomtemperature for 23 hours. The reaction solution was poured into waterand extracted with ethyl acetate. The organic layer was washed with 1Nhydrochloric acid, water and brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=9:1→5:1) to givethe title compound (629 mg) having the following physical data.

TLC: Rf 0.65 (n-hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 7.92 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 4.16 (q,J=7.2 Hz, 2H), 3.29 (t, J=6.6 Hz, 2H), 2.75 (t, J=6.6 Hz, 2H), 1.34 (s,9H), 1.26 (t, J=7.2 Hz, 3H).

EXAMPLE 32-(2-(2-(4-t-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 10 (270 mg) in ethanol (5 mL) was added sodiumhydrogen carbonate (84 mg) and the mixture was stirred for 10 minutes.And then acetic acid(0.12 mL) and the compound prepared in ReferenceExample 11 (262 mg) were added thereto and the mixture was stirred atroom temperature for 15 minutes. Sodium cyanoborohydride (125 mg) wasadded to the reaction solution, which was stirred at 70° C. overnight.Water was added to the reaction solution, which was extracted with ethylacetate. The organic layer was washed with water and brine, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=1:12:3)to give the compound of the present invention (170 mg) having thefollowing physical data.

TLC: Rf 0.28 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.99 (s, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz,2H), 4.79 (dd, J=7.8, 5.4 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.93 (dt,J=14.4, 7.2 Hz, 1H), 3.45-3.28 (m, 2H), 3.01 (dt,J=14.4, 6.9 Hz, 1H),2.64-2.33 (m, 3H), 1.90 (m, 1H), 1.40 (t, J=7.2 Hz, 3H), 1.30 (s, 9H).

EXAMPLE 3(1) TO 3(13)

By the same procedure as described in Example 3, using a correspondingderivative instead of the compound prepared in Reference Example 11, thefollowing compounds of the present invention were obtained.

EXAMPLE 3(1)2-(2-(2-(4-n-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.64 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.00 (s, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz,2H), 4.79 (dd, J=7.5, 5.4 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.93 (dt,J=14.1, 7.2 Hz, 1H), 3.37 (m, 2H), 3.01 (dt, J=14.1, 6.3 Hz, 1H),2.64-2.35 (m, 5H), 1.90 (m, 1H), 1.55 (m, 2H), 1.40 (t, J=7.2 Hz, 3H),1.35 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 3(2)2-(2-(2-(4-(1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.80 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 7.99 (s, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz,2H), 4.82 (m, 1H), 4.65 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.91 (m, 1H),3.36 (m, 2H), 3.02 (m, 1H), 2.65-2.35 (m, 3H), 2.10-1.55 (m, 6H), 1.40(t, J=7.2 Hz, 3H), 1.40-1.15 (m, 4H), 0.87 (t, J=6.6 Hz, 3H).

EXAMPLE 3(3)2-(2-(2-(4-propoxyphenyl)-5-oxopyrrolidin-1-:yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.15 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.00 (s, 1H), 7.11 (d, J=9.0 Hz, 2H), 6.84 (d, J=9.0 Hz,2H), 4.76 (dd, J=7.8, 5.4 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.94-3.81 (m,3H), 3.44-3.28 (m, 2H), 3.01 (dt, J=14.4, 6.9 Hz, 1H), 2.60-2.35 (m,3H), 1.88 (m, 1H), 1.80 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.03(t, J=7.2 Hz, 3H).

EXAMPLE 3(4)2-(2-(2-(1,1′-biphenyl-4-yl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid methyl ester

TLC: Rf 0.23 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.98 (s, 1H), 7.62-7.52 (m, 4H), 7.49-7.32 (m, 3H),7.31-7.24 (m, 2H), 4.89 (t, J=6.3 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 3.98(dt, J=14.4, 7.2 Hz, 1H), 3.46-3.37 (m, 2H), 3.06 (dt, J=14.4, 6.9 Hz,1H), 2.64-2.37 (m, 3H), 1.95 (m, 1H), 1.38 (t, J=7.2 Hz, 3H).

EXAMPLE 3(5)2-(2-(2-(4-n-hexylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.34 (ethyl acetate:n-hexane=1:1);

NMR (CDCl₃): δ 8.00 (s, 1H), 7.21-7.26 (m, 4H), 4.82-4.75 (m, 1H), 4.41(q, J=6.9 Hz, 2H), 3.98-3.87 (m, 1H), 3.44-3.29 (m, 2H), 3.07-2.95 (m,1H), 2.63-2.33 (m, 5H), 1.97-1.84 (m, 1H), 1.65-1.51 (m, 2H), 1.46-1.21(m, 9H), 0.93-0.82 (m, 3H).

EXAMPLE 3(6)2-(2-(2-(4-n-propylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.21 (ethyl acetate:n-hexane=1:1);

NMR (CDCl₃): δ 8.00 (s, 1H), 7.15-7.09 (m, 4H), 4.79 (dd, J=7.5, 5.7 Hz,1H), 4.41 (q, J=7.2 Hz, 2H), 3.93 (dt, J=14.1, 7.2 Hz, 1H), 3.42-3.39(m, 2H), 3.00 (dt, J=14.1, 6.6 Hz, 1H), 2.60-2.35 (m, 5H), 1.96-1.83 (m,1H), 1.68-1.55 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H).

EXAMPLE 3(7)2-(2-(2-phenyl-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acidethyl ester

TLC: Rf 0.15 (ethyl acetate:n-hexane=1:1);

NMR (CDCl₃):δ 8.00 (s, 1H), 7.36-7.27 (m, 3H), 7.24-7.16 (m, 2H), 4.83(t, J=6.9 Hz, 1H), 4.40 (q, J=6.9 Hz, 2H), 3.95 (dt, J=14.1, 7.2 Hz,1H), 3.46-3.30 (m, 2H), 3.01 (dt, J=14.1, 6.3 Hz, 1H), 2.64-2.35 (m,3H), 1.99-1.83 (m, 1H), 1.40 (t, J=6.9 Hz, 3H).

EXAMPLE 3(8)2-(2-(2-(4-ethylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.17 (ethyl acetate:n-hexane=1:1);

NMR (CDCl₃): δ 8.00 (s, 1H), 7.20-7.07 (m, 4H), 4.79 (dd, J=7.5, 5.4 Hz,1H), 4.40 (q, J=7.2 Hz, 2H), 3.93 (dt, J=14.1, 6.9 Hz, 1H), 3.37 (dt,J=6.6, 1.8 Hz, 2H), 3.01 (dt, J=14.1, 6.3 Hz, 1H), 2.66-2.37 (m, 5H),1.96-1.84 (m, 1H), 1.40 (t, J=6.9 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H).

EXAMPLE 3(9)2-(2-(2-(4-n-pentylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.31 (ethyl acetate:n-hexane=1:1);

NMR (CDCl₃): δ 8.00 (s, 1H), 7.15-7.08 (m, 4H), 4.78 (dd, J=8.1, 5.7 Hz,1H), 4.41 (q, J=7.2 Hz, 2H), 3.98-3.86 (m, 1H), 3.37 (dt, J=6.6, 2.4 Hz,2H), 3.06-2.95 (m, 1H), 2.63-2.35 (m, 5H), 1.97-1.86 (m, 1H), 1.40 (t,J=7.2 Hz, 3H), 1.37-1.26 (m, 4H), 0.91-0.85 (m, 3H).

EXAMPLE 3(10)2-(2-(2-(4-methylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.33 (ethyl acetate:n-hexane=1:1);

NMR(CDCl₃): δ 8.00 (s, 1H), 7.20-7.05 (m, 4H), 4.82-4.75 (m, 1H), 4.40(q, J=6.9 Hz, 2H), 3.98-3.86 (m, 1H), 3.37 (dt, J=6.3, 2.1 Hz, 2H),3.06-2.96 (m, 1H), 2.63-2.35 (m, 6H), 1.96-1.83 (m, 1H), 1.40 (t, J=6.9Hz, 3H).

EXAMPLE 3(11)2-(2-(2-(4-n-octylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.25 (ethyl acetate:n-hexane=1:1);

NMR(CDCl₃): δ 8.00 (s, 1H), 7.20-7.09 (m, 4H), 4.82-4.76 (m, 1H), 4.41(q, J=7.2 Hz, 2H), 3.98-3.87 (m, 1H), 3.37 (dt, J=6.3, 2.4 Hz, 2H),3.06-2.96 (m, 1H), 2.62-2.32 (m, 5H), 1.97-1.84 (m, 1H), 1.65-1.52 (m,2H), 1.40 (t, J=7.2 Hz, 3H), 1.35-0.92-0.85 (m, 3H).

EXAMPLE 3(12)2-(2-(2-(4-n-heptylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.32 (ethyl acetate:n-hexane=1:1);

NMR(CDCl₃): δ 8.00 (s, 1H), 7.19-7.05 (m, 4H), 4.82-4.76 (m, 1H), 4.40(q, J=7.2 Hz, 2H), 3.98-3.87 (m, 1H), 3.37 (dt, J=6.6, 2.1 Hz, 2H),3.06-2.95 (m, 1H), 2.63-2.34 (m, 5H), 1.98-1.85 (m, 1H), 1.66-1.52 (m,2H), 1.40 (t, J=7.2 Hz, 3H), 1.37-1.21 (m, 8H), 0.95-0.82 (m, 3H).

EXAMPLE 3(13)2-(2-(2-(3-n-hexylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.32 (ethyl acetate:n-hexane=1:1);

NMR(CDCl₃): δ 8.00 (s, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.13-7.08 (m, 1H),7.03-6.97 (m, 2H), 4.82-4.76 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.99-3.89(m, 1H), 3.38 (dt, J=6.6, 1.2 Hz, 2H), 3.07-2.97 (m, 1H), 2.62-2.36 (m,5H), 1.97-1.85 (m, 1H), 1.63-1.51 (m, 2H, 1.40 (t, J=7.2 Hz, 3H),1.37-1.22 (m, 6H), 0.92-0.83 (m, 3H).

EXAMPLE 4 to 4(13)

By the same procedure as described in Example 2, using the compoundprepared in Example 3 to 3(13) instead of the compound prepared inExample 1, the following compounds of the present invention wereobtained.

EXAMPLE 42-(2-(2-(4-t-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.29 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.07 (s, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz,2H), 4.68 (dd, J=7.5, 6.0 Hz, 1H), 3.97 (m, 1H), 3.30-3.10 (m, 3H),2.69-2.39 (m, 3H), 1.95 (m, 1H), 1.32 (s, 9H).

EXAMPLE 4(1)2-(2-(2-(4-n-butylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.25 (chloroform:methanol:acetic acid=200:20:1);

NMR (CDCl₃): δ 8.07 (s, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz,2H), 4.67 (dd, J=7.8, 6.0 Hz, 1H), 3.94 (m, 1H), 3.30-3.05 (m, 3H),2.70-2.40 (m, 5H), 1.95 (m, 1H), 1.60 (m, 2H), 1.36 (m, 2H), 0.93 (t,J=7.5 Hz, 3H).

EXAMPLE 4(2)2-(2-(2-(4-(1-hydroxyhexyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.51 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 8.07 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.1 Hz,2H), 4.77-4.63 (m, 2H), 3.96 (m, 1H), 3.35-3.07 (m, 3H), 2.71-2.40 (m,3H), 2.02-1.58 (m, 3H), 1.55-1.17 (m, 6H), 0.87 (t, J=6.6 Hz, 3H).

EXAMPLE 4(3)2-(2-(2-(4-propoxyphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.35 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.14 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz,2H), 4.65 (dd, J=7.5, 6.6 Hz, 1H), 3.92 (t, J=6.6 Hz, 2H), 3.89 (m,1H),3.32-3.05 (m, 3H), 2.69-2.38 (m, 3H), 1.95 (m, 1H), 1.81 (m , 2H), 1.04(t, J=7.5 Hz, 3H).

EXAMPLE 4(4) 2-(2-(2-(1,1′-biphenyl-4-yl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.31 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.07 (s, 1H), 7.65-7.55 (m, 4H), 7.49-7.41 (m, 2H),7.40-7.27 (m, 3H), 4.76 (dd, J=7.8, 5.7 Hz, 1H), 4.01 (m, 1H), 3.38-3.11(m, 3H), 2.76-2.43 (m, 3H), 2.00 (m, 1H).

EXAMPLE 4(5)2-(2-(2-(4-n-hexylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.26 (methylene chloride:methanol=5:1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.22-7.10 (m, 4H), 4.72-4.65 (m, 1H),4.00-3.85 (m, 1H), 3.31-3.08 (m, 3H), 2.71-2.40 (m, 5H), 2.02-1.89 (m,1H), 1.67-1.54 (m, 2H), 1.43-1.24 (m, 6H), 0.95-0.83 (m, 3H).

EXAMPLE 4(6)2-(2-(2-(4-n-propylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.24 (methylene chloride:methanol=5:1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.22-7.11 (m, 4H), 4.72-4.65 (m, 1H),4.00-3.86 (m, 1H), 3.44-3.09 (m, 3H), 2.70-2.40 (m, 5H), 2.01-1.89 (m,1H), 1.70-1.57 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 4(7)2-(2-(2-phenyl-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylic acid

TLC: Rf 0.21 (methylene chloride:methanol=5:1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.42-7.31 (m, 3H), 7.28-7.20 (m, 2H),4.76-4.70 (m, 1H), 4.02-3.89 (m, 1H), 3.34-3.10 (m, 3H), 2.71-2.42 (m,3H), 2.02-1.90 (m, 1H).

EXAMPLE 4(8)2-(2-(2-(4-ethylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.17 (methylene chloride:methanol=5:1);

NMR (CDCl₃): δ 8.07 (s, 1H), 7.22-7.10 (m, 4H), 4.70-4.64 (m, 1H),4.01-3.88 (m, 1H), 3.29-3.12 (m, 3H), 2.71-2.41 (m, 5H), 2.01-1.89 (m,1H), 1.25 (t, J=7.5 Hz, 3H).

EXAMPLE 4(9)2-(2-(2-(4-n-pentylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.23 (methylene chloride:methanol=5:1);

NMR (CDCl₃): δ 8.84 (brs, 1H), 8.08 (s, 1H), 7.22-7.09 (m, 4H),4.74-4.67 (m, 1H), 3.98-3.87 (m, 1H), 3.35-3.12 (m, 3H), 2.69-2.40 (m,5H), 2.03-1.88 (m, 1H), 1.66-1.55 (m, 2H), 1.42-1.25 (m, 4H), 0.93-0.85(m, 3H).

EXAMPLE 4(10)2-(2-(2-(4-methylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.17 (dichloroethane:methanol=5:1);

NMR(CDCl₃): δ 8.07 (s, 1H), 7.22-7.09 (m, 4H), 4.70-4.63 (m, 1H),3.98-3.85 (m, 1H), 3.30-3.03 (m, 3H), 2.69-2.41 (m, 3H), 2.36 (s, 3H),2.01-1.88 (m, 1H).

EXAMPLE 4(11)2-(2-(2-(4-n-octylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.32 (dichloroethane:methanol=5:1);

NMR(CDCl₃): δ 8.08 (s, 1H), 7.22-7.09 (m, 4H), 4.70-4.63 (m, 1H),4.00-3.89 (m, 1H), 3.31-3.08 (m, 3H), 2.67-2.40 (m, 5H), 2.01-1.90 (m,1H), 1.68-1.54 (m, 2H), 1.39-1.16 (m, 10H), 0.96-0.82 (m, 3H).

EXAMPLE 4(12)2-(2-(2-(4-n-heptylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.16 (dichloroethane:methanol=5:1);

NMR(CDC₃): δ 9.22 (brs, 1H), 8.09 (s, 1H), 7.23-7.09 (m, 4H), 4.75-4.68(m, 1H), 4.01-3.86 (m, 1H), 3.36-3.12 (m, 3H), 2.69-2.39 (m, 5H),2.02-1.89 (m, 1H), 1.67-1.53 (m, 2H), 1.39-1.20 (m, 8H), 0.92-0.83 (m,3H).

EXAMPLE 4(13)2-(2-(2-(3-n-hexylphenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.32 (dichloroethane:methanol=5:1);

NMR(CDCl₃): δ 8.08 (s, 1H), 7.29 (t, J=8.1 Hz, 1H), 7.18-7.13 (m, 1H),7.06-7.00 (m, 2H), 4.71-4.65 (m, 1H), 4.01-3.90 (m, 1H), 3.30-3.07 (m,3H), 2.69-2.41 (m, 5H), 2.02-1.89 (m, 1H), 1.64-1.52 (m, 2H), 1.37-1.22(m, 6H), 0.91-0.82 (m, 3H).

EXAMPLE 5(1) TO 5(45)

By the same procedure as described in Example 1, using the compoundprepared in Reference Example 3 or a corresponding aldehyde derivative,and the compound prepared in Reference Example 9 or a correspondingamine derivative, the following compounds of the present invention wereobtained.

EXAMPLE 5(1)(13E,16α)-17,17-propano-16-hydroxy-5-(4-methoxycarbonyloxazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-8-azaprost-13-ene

TLC: Rf 0.07 (ethyl acetate);

NMR (CDCl₃): δ 8.14 (s, 1H), 5.78 (dt, J=15.0, 7.5 Hz, 1H), 5.37 (dd,J=15.0, 9.0 Hz, 1H), 4.05 (m, 1H), 3.90 (s, 3H), 3.62-3.49 (m, 2H), 3.05(m, 1H), 2.80 (t, J=7.5 Hz, 2H), 2.49-2.14 (m, 4H), 2.10-1.52 (m, 11H),1.44 (m, 1H), 0.91 (t, J=7.5 Hz, 3H).

EXAMPLE 5(2)5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-14,15-(1,4-interphenylene)-1,2,3,4-tetranor-5-thia-8-azaprostane

TLC: Rf 0.19 (ethyl acetate:n-hexane=1:1);

NMR (CDCl₃): δ 7.99 (s, 1H), 7.10-7.01 (m, 4H), 4.43-4.34 (m, 3H),3.44-3.28 (m, 3H), 3.08-2.94 (m, 1H), 2.89-2.41 (m, 8H), 1.84-1.48 (m,4H), 1.41-1.19 (m, 9H), 0.92-0.81 (m, 3H).

EXAMPLE 5(3)(13E)-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,18,19,20-heptanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.29 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.03 (s, 1H), 5.65 (dt, J=15.3, 6.6 Hz, 1H), 5.22 (dd,J=15.3, 8.7 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.83 (dt,J=13.5, 6.9 Hz, 1H), 3.50-3.40 (m, 2H), 3.30 (dt, J=13.5, 6.9 Hz, 1H),2.46-2.10 (m, 3H), 2.02-1.90 (m, 2H), 1.72 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.38-1.28 (m, 2H), 0.85 (t, J=7.2 Hz, 3H).

EXAMPLE 5(4)(13E)-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.30 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.65 (dt, J=15.3, 6.6 Hz, 1H), 5.21 (dd,J=15.3, 8.7 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.83 (dt,J=13.5, 6.9 Hz, 1H), 3.50-3.39 (m, 2H), 3.29 (dt, J=13.5, 6.9 Hz, 1H),2.46-2.10 (m, 3H), 2.04-1.93 (m, 2H), 1.72 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.36-1.17 (m, 4H), 0.86 (t, J=7.2 Hz, 3H).

EXAMPLE 5(5)(2E,13E,16α)-17,17-propano-16-hydroxy-3,6-(1,4-interphenylene)-9-oxo-4,5,20-trinor-8-azaprost-2,13-dienoicacid ethyl ester

TLC: Rf 0.30(ethyl acetate);

NMR (CDCl₃): δ 7.65 (d, J=16.0 Hz, 1H), 7.45 (d, J=9.0 Hz, 2H), 7.20 (d,J=9.0 Hz, 2H), 6.40 (d, J=16.0 Hz, 1H), 5.67 (dt, J=15.4, 7.2 Hz, 1H),5.28 (dd, J=15.4, 8.7 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.88-3.70 (m,2H), 3.57 (m, 1H), 3.15 (m, 1H), 2.95-2.70 (m, 2H), 2.50-1.40 (m, 15H),1.35 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 5(6)(13E,16α)-17,17-propano-16-hydroxy-1,7-(2,5-interthienylene)-9-oxo-2,3,4,5,6,20-hexanor-8-azaprost-13-enoicacid methyl ester

TLC: Rf 0.58(chloroform:methanol=9:1);

NMR (CDCl₃): δ 0.93 (t, J=7.2 Hz, 3 H), 1.73 (m, 11H), 2.35 (m, 4 H),3.55 (m, 1H), 3.86 (s, 3 H), 4.01 (m, 1H), 4.20 (d, J=15.4 Hz, 1H), 4.92(d, J=15.4 Hz, 1H), 5.37 (dd, J=15.0, 9.0 Hz, 1H), 5.78 (dt, J=15.0, 7.2Hz, 1H), 6.93 (m, 1H), 7.64 (m, 1H).

EXAMPLE 5(7)(13E)-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.36 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.66 (dt, J=15.3, 6.6 Hz, 1H), 5.21 (dd,J=15.3, 8.7 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.83 (dt,J=13.5, 6.9 Hz, 1H), 3.50-3.40 (m, 2H), 3.29 (dt, J=13.5, 6.9 Hz, 1H),2.46-2.12 (m, 3H), 2.03-1.91 (m, 2H), 1.72 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.38-1.17 (m, 8H), 0.87 (t, J=7.2 Hz, 3H).

EXAMPLE 5(8)(13E)-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-20-methyl-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.37 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.66 (dt, J=15.0, 6.6 Hz, 1H), 5.21 (dd,J=15.0, 9.0 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.83 (dt,J=13.8, 6.9 Hz, 1H), 3.50-3.40 (m, 2H), 3.29 (dt, J=13.8, 6.9 Hz, 1H),2.46-2.12 (m, 3H), 2.03-1.93 (m, 2H), 1.72 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.38-1.16 (m, 1OH), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 5(9)(13E,15α)-15-hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-8-azaprost-13-enoicacid methyl ester

TLC: Rf 0.18 (ethyl acetate);

NMR (CDCl₃): δ 0.89 (m, 3 H) 1.49 (m, 9 H) 2.12 (m, 1 H) 2.35 (m, 2 H)2.87 (m, 2 H) 3.12 (m, 1 H) 3.79 (m, 2 H) 3.91 (s, 3 H) 4.11 (m, 1H)5.38 (dd, J=15.38, 8.52 Hz, 1 H) 5.58 (dd, J=15.38, 6.32 Hz, 1 H) 7.25(d, J=7.69 Hz, 2 H) 7.96 (d, J=7.97 Hz, 2 H).

EXAMPLE 5(10) (13E,15α)-15-hydroxy-1,5-(2,5-interthienylene)-9-oxo-2,3,4-trinor-8-azaprost-13-enoic acidmethyl ester

TLC: Rf 0.26 (ethyl acetate);

NMR (CDCl₃): δ 0.89 (t, J=6.59 Hz, 3 H) 1.40 (m, 9 H) 1.80 (m, 3 H) 2.31(m, 2 H) 2.83 (t, J=7.69 Hz, 2 H) 2.98 (m, 1 H) 3.58 (m, 1 H) 3.86 (s, 3H) 4.08 (m, 3 H) 5.48 (dd, J=15.38, 8.79 Hz, 1 H) 5.68 (dd, J=15.38,6.32 Hz, 1 H) 6.81 (d, J=3.85 Hz, 1 H) 7.62 (d, J=3.85 Hz, 1 H).

EXAMPLE 5(11) (13E,15α)-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic acidethyl ester

TLC: Rf 0.30 (ethyl acetate);

NMR (CDCl₃): δ 0.89 (m, 3 H) 1.41 (m, 8 H) 1.81 (m, 4 H) 2.32 (m, 5 H)2.63 (m, 4 H) 3.11 (m, 1 H) 3.67 (m, 1 H) 4.13 (m, 4 H) 5.53 (dd,J=15.38, 8.24 Hz, 1 H) 5.74 (dd, J=15.38, 5.77 Hz, 1 H).

EXAMPLE 5(12)(13E)-5-(4-ethoxycarbonylthiazol-2-yl)-9,15-dioxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.38 (ethyl acetate);

NMR (CDCl₃): δ 8.02 (s, 1H), 6.58 (dd, J=15.6, 7.8 Hz, 1H), 6.24 (d,J=15.6 Hz, 1H), 4.52-4.35 (m, 3H), 3.99-3.88 (m, 1H), 3.53-3.37 (m, 2H),3.29-3.19 (m, 1H), 2.51 (t, J=7.5 Hz, 2H), 2.47-2.22 (m, 3H), 1.89-1.78(m, 1H), 1.61-1.50 (m, 2H), 1.42-1.23 (m, 5H), 0.90 (t, J=7.5 Hz, 3H).

EXAMPLE 5(13)5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprostane

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 4.39 (q, J=7.2 Hz, 2H), 3.89 (m, 1H), 3.71(m, 1H), 3.54-3.31 (m, 3H), 2.46-2.22 (m, 2H), 2.12 (m, 1H), 1.78-1.60(m, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.38-1.16 (m, 11H), 0.87 (t, J=7.2 Hz,3H).

EXAMPLE 5(14)(13E,15α)-20-ethyl-15-hydroxy-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.40 (ethyl acetate);

NMR (CDCl₃): δ 0.88 (m, 3 H) 0.97 (t, J=7.42 Hz, 3 H) 1.27 (m, 10 H)1.45 (m, 4 H) 1.76 (m, 3 H) 1.95 (d, J=4.40 Hz, 1 H) 2.30 (m, 3 H) 3.41(m, 3 H) 3.76 (m, 1 H) 4.08 (m, 1 H) 4.22 (m, 1 H) 4.33 (m, 2 H) 5.55(m, 1H) 5.79 (m, 1 H) 7.99 (d, J=3.02 Hz, 1 H).

EXAMPLE 5(15)(13E,15α)-20-methyl-15-hydroxy-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.32 (ethyl acetate);

NMR (CDCl₃): δ 7.99 (s, 1H), 5.79 (dd, J=15.3, 5.7 Hz, 1H), 5.54 (ddd,J=15.3, 8.4, 1.2 Hz, 1H), 4.33 (t, J=6.9 Hz, 2H), 4.26-4.16 (m, 1H),4.14-4.04 (m, 1H), 3.80-3.70 (m, 1H), 3.50-3.30 (m, 4H), 2.45-2.15 (m,3H), 1.95-1.90 (m, 1H), 1.80-1.65 (m, 3H), 1.50-1.40 (m, 3H), 1.35-1.20(m, 8H), 0.97 (t, J=7.2 Hz, 3H), 0.90-0.80 (m, 3H),

EXAMPLE 5(16)(13E,15α)-20-n-propyl-15-hydroxy-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.32 (ethyl acetate);

NMR (CDCl₃): δ 7.99 (s, 1H), 5.78 (dd, J=15.6, 5.7 Hz, 1H), 5.54 (ddd,J=15.6, 8.4, 1.2 Hz, 1H), 4.33 (t, J=6.9 Hz, 2H), 4.26-4.16 (m, 1H),4.14-4.04 (m, 1H), 3.80-3.70 (m, 1H), 3.50-3.30 (m, 4H), 2.45-2.15 (m,3H), 1.95-1.90 (m, 1H), 1.80-1.65 (m, 3H), 1.50-1.40 (m, 3H), 1.35-1.20(m, 12H), 0.97 (t, J=7.2 Hz, 3H), 0.90-0.80 (m, 3H),

EXAMPLE 5(17)(13Z)-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.28 (hexane:ethyl acetate=1:2);

NMR (CDCl₃) δ 8.02 (s, 1H), 5.59 (dt, J=10.5, 7.8 Hz, 1H), 5.22 (dd,J=10.5, 9.9 Hz, 1H), 4.53 (dt, J=9.9, 6.9 Hz, 1H), 4.39 (q, J=7.2 Hz,2H), 3.77 (dt, J=14.1, 6.3 Hz, 1H), 3.45 (t, J=6.3 Hz, 2H), 3.33 (dt,J=14.1, 6.3 Hz, 1H), 2.45-1.93 (m, 5H), 1.67 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.38-1.16 (m, 6H), 0.87 (t, J=7.2 Hz, 3H).

EXAMPLE 5(18)(13Z)-16-oxa-17,17-dimethyl-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.20 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.76 (dt, J=11.1, 6.3 Hz, 1H), 5.37 (dd,J=11.1, 9.9 Hz, 1H), 4.64 (dt, J=9.9, 6.6 Hz, 1H), 4.39 (q, J=7.2 Hz,2H), 4.04-3.90 (m, 2H), 3.82 (dt, J=13.5, 6.3 Hz, 1H), 3.54-3.41 (m,2H), 3.35 (dt, J=13.5, 6.3 Hz, 1H), 2.48-2.13 (m, 3H), 1.71 (m, 1H),1.39 (t, J=7.2 Hz, 3H), 1.19 (s, 9H).

EXAMPLE 5(19)(13E)-16-oxa-17,17-dimethyl-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.20 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.77 (dt, J=15.3, 5.1 Hz, 1H), 5.50 (dd,J=15.3, 9.0 Hz, 1H), 4.40 (q, J=7.2, Hz, 2H), 4.20 (dt, J=5.1, 8.1 Hz,1H), 3.90-3.78 (m, 3H), 3.44 (t, J=6.3 Hz, 2H), 3.31 (dt, J=13.2, 6.3Hz, 1H), 2.48-2.12 (m, 3H), 1.77 (m, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.18(s, 9H).

EXAMPLE 5(20)(13E,15α)-19-phenyl-15-hydroxy-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.27 (ethyl acetate);

NMR (CDCl₃): δ 0.96 (t, J=7.14 Hz, 3 H) 1.51 (m, 11 H) 2.00 (d, J=4.67Hz, 1 H) 2.29 (m, 3 H) 2.58 (t, J=7.69 Hz, 2 H) 3.37 (m, 3 H) 3.76 (m, 1H) 4.14 (m, 2 H) 4.31 (t, J=6.59 Hz, 2 H) 5.54 (ddd, J=15.38, 8.52, 1.10Hz, 1 H) 5.78 (dd, J=15.66, 5.77 Hz, 1 H) 7.21 (m, 5 H) 7.98 (s, 1 H).

EXAMPLE 5(21)(13E,15α)-20-phenyl-15-hydroxy-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.29 (ethyl acetate);

NMR (CDCl₃): δ 0.97 (t, J=7.42 Hz, 3 H) 1.52 (m, 13 H) 1.97 (d, J=4.67Hz, 1 H) 2.31 (m, 3 H) 2.59 (t, J=7.14 Hz, 2 H) 3.40 (m, 3 H) 3.77 (m,1H) 4.14 (m, 2 H) 4.32 (t, J=6.87 Hz, 2 H) 5.54 (ddd, J=15.38, 8.52,1.10 Hz, 1 H) 5.79 (dd, J=15.38, 5.49 Hz, 1 H) 7.22 (m, 5 H) 7.95 (s,1H).

EXAMPLE 5(22)(13E,15α)-20-benzyl-15-hydroxy-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.29 (ethyl acetate);

NMR (CDCl₃): δ 0.97 (t, J=7.42 Hz, 2 H) 1.52 (m, 15 H) 1.96 (d, J=4.67Hz, 1 H) 2.31 (m, 3 H) 2.59 (t, J=7.42 Hz, 2 H) 3.39 (m, 3 H) 3.77 (m, 1H) 4.14 (m, 2 H) 4.32 (t, J=6.87 Hz, 2 H) 5.55 (ddd, J=15.66, 8.79, 1.10Hz, 1 H) 5.78 (dd, J=15.66, 5.77 Hz, 1 H) 7.23 (m, 5 H) 7.97 (s, 1 H).

EXAMPLE 5(23)(13E,16α)-17,17-propano-16-hydroxy-1,6-(1,3-interphenylene)-9-oxo-2,3,4,5,20-pentanor-8-azaprost-13-enoicacid methyl ester

TLC: Rf 0.29(ethyl acetate);

NMR (CDCl₃): δ 0.92 (t, J=7.4 Hz, 3 H), 1.43 (m, 1 H), 2.00 (m, 14 H),2.80 (m, 1 H), 2.92 (m, 1 H), 3.15 (m, 1 H), 3.57 (dd, J=9.7, 2.3 Hz, 1H), 3.76 (m, 1 H), 3.88 (m, 1 H), 3.91 (m, 3 H), 5.26 (dd, J=15.2, 8.9Hz, 1 H), 5.79 (dt, J=15.2, 7.2 Hz, 1 H), 7.39 (m, 2 H), 7.89 (m, 2 H).

EXAMPLE 5(24)(15α)-15-hydroxy-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprostane

TLC: Rf 0.20 (ethyl acetate);

NMR (CDCl₃): δ 0.89 (t, J=6.59 Hz, 3 H) 1.48 (m, 15 H) 1.97 (m, 1 H)2.14 (m, 1 H) 2.36 (m, 2 H) 2.53 (d, J=5.22 Hz, 1 H) 3.60 (m, 6 H) 4.38(q, J=7.14 Hz, 2 H) 7.99 (s, 1 H).

EXAMPLE 5(25)(15α)-15-hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-5-thia-8-azaprostanoicacid methyl ester

TLC: Rf 0.20 (ethyl acetate);

NMR (CDCl₃): δ 0.90 (t, J=6.59 Hz, 3 H) 1.47 (m, 13 H) 2.04 (m, 1 H)2.32 (m, 2 H) 2.87 (m, 2 H) 3.06 (m, 1 H) 3.40 (m, 1 H) 3.57 (m, 1 H)3.86 (m, 4 H) 7.30 (d, J=8.52 Hz, 2 H) 7.97 (d, J=8.52 Hz, 2 H).

EXAMPLE 5(26)(13E)-17,17-dimethyl-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.20 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.67 (dt, J=15.0, 6.9 Hz, 1H), 5.21 (dd,J=15.0, 8.7 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.83 (dt,J=13.5, 6.9 Hz, 1H), 3.50-3.37 (m, 2H), 3.3b (dt, J=13.5, 6.9 Hz, 1H),2.46-2.11 (m, 3H), 2.00-1.89 (m, 3H), 1.71 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.22-1.12 (m, 2H), 0.86 (s, 9H).

EXAMPLE 5(27)(13E)-17,17-dimethyl-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.20 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.67 (dt, J=15.0, 6.9 Hz, 1H), 5.21 (dd,J=15.0, 8.7 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.83 (dt,J=13.5, 6.6 Hz, 1H), 3.50-3.38 (m, 2H), 3.30 (dt, J=13.5, 6.6 Hz, 1H),2.47-2.08 (m, 3H), 1.96-1.84 (m, 3H), 1.72 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.24-1.18 (m, 2H), 0.86-0.71 (m, 9H).

EXAMPLE 5(28)(13E,15α)-19-phenyl-15-hydroxy-9-oxo-20-nor-5-thia-8-azaprost-13-enoicacid butyl ester

TLC: Rf 0.33 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.32-7.24 (m, 2H), 7.21-7.14 (m, 3H), 5.72 (dd, J=15.3,6.0 Hz, 1 H), 5.50 (ddd, J=15.3, 9.0, 0.6 Hz, 1H), 4.20-4.00 (m, 4H),3.70-3.60 (m, 1H), 3.10-3.00 (m, 1H), 2.70-2.50 (m, 6H), 2.45-2.15 (m,5H), 1.95-1.30 (m, 14H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 5(29)(13E,15α)-20-phenyl-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic-acidbutyl ester

TLC: Rf 0.33 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.30-7.23 (m, 2H), 7.20-7.13 (m, 3H), 5.73 (dd, J=15.3,5.7 Hz, 1H), 5.51 (ddd, J=15.3, 8.7, 1.2 Hz, 1H), 4.20-4.05 (m, 4H),3.75-3.60 (m, 1H), 3.15-3.05 (m, 1H), 2.70-2.50 (m, 6H), 2.45-2.15 (m,5H), 1.95-1.30 (m, 16H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 5(30)(13E,15α)-20-benzyl-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic acidbutyl ester

TLC: Rf 0.33 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.30-7.22 (m, 2H), 7.20-7.15 (m, 3H), 5.73 (dd, J=15.3,5.7 Hz, 1H), 5.52 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.20-4.05 (m, 4H),3.72-3.60 (m, 1H), 3.15-3.05 (m, 1H), 2.70-2.20 (m, 11H), 1.95-1.20 (m,18H), 0.93 (t, J=7.5 Hz, 3H).

EXAMPLE 5(31)14-oxa-14-phenyl-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.45 (ethyl acetate);

NMR (CDCl₃): δ 7.97 (s, 1H), 7.25 (dd, J=8.7, 7.5 Hz, 2H), 6.94 (t,J=7.5 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 4.37 (dd, J=9.9,3.6 Hz, 1H),4.35-4.27 (m, 2H), 4.14 (m, 1H), 4.00 (dd, J=9.9, 3.6 Hz, 1H), 3.64-3.32(m, 3H), 2.58 (m, 1H), 2.37 (m, 1H), 2.22 (m, 1H), 2.03 (m, 1H),1.80-1.68 (m, 2H), 1.52-1.37 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).

EXAMPLE 5(32)14-oxa-14-(3,5-dichlorophenyl)-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.53 (ethyl acetate);

NMR (CDCl₃): δ 7.97 (s, 1H), 6.93 (t, J=1.8 Hz, 1H), 6.87 (d, J=1.8 Hz,2H), 4.69 (dd, J=10.2, 3.0 Hz, 1H), 4.38-4.30 (m, 2H), 4.12 (m, 1H),4.00 (dd, J=10.2, 3.0 Hz, 1H), 3.84 (m, 1H), 3.61 (m, 1H), 3.4 7 (m,1H), 3.26 (m, 1H), 2.57 (m, 1H), 2.39 (m, 1H), 2.23 (m, 1H), 2.06 (m,1H), 1.80-1.69 (m, 2H), 1.52-1.38 (m, 2H), 0.97 (t, J=7.2 Hz, 3H).

EXAMPLE 5(33) (13E,16α)-17,17-propano-16-hydroxy-6-(4-ethoxycarbonylthiazol-2-ylsulfonyl)-9-oxo-1,2,3,4,5,20-hexanor-8-azaprost-13-ene

TLC: Rf 0.33 (ethyl acetate);

NMR (CDCl₃): δ 0.93 (t, J=7.5 Hz, 3 H), 1.42 (m, 1 H), 1.42 (t, J=7.2Hz, 3 H), 1.84 (m, 10 H), 2.29 (m, 4 H), 3.75 (m, 5 H), 4.22 (m, 1 H),4.45 (q, J=7.2 Hz, 2 H), 5.39 (dd, J=15.1, 9.0 Hz, 1 H), 5.93 (d t,J=15.1, 7.2 Hz, 1 H), 8.47 (s, 1 H).

EXAMPLE 5(34)14-oxa-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprostane

TLC: Rf 0.47 (ethyl acetate);

NMR (CDCl₃): δ 0.88 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H), 1.23-1.58(m, 7H), 1.69-1.89 (m, 3H), 2.09 (m, 1H), 2.28 (m, 1H), 2.44 (m, 1H),3.37-3.60 (m, 6H), 3.63 (dd, J=10.2, 3.6 Hz, 1H), 3.84-3.97 (m, 2H),4.33 (t, J=6.6 Hz, 2H), 8.00 (s, 1H).

EXAMPLE 5(35)17,17-propano-5-(4-ethoxycarbonylthiazol-2-yl)-9,16-dioxo-1,2,3,4,20-pentanor-5-thia-8-azaprostane

TLC: Rf 0.41 (ethyl acetate);

NMR (CDCl₃): δ 0.74 (t, J=7.5 Hz, 3 H), 1.39 (t, J=7.1 Hz, 3 H), 1.56(m, 1H), 1.65-2.00 (m, 9 H), 2.10-2.55 (m, 8 H), 3.35-3.55 (m, 3 H),3.72 (m, 1 H), 3.88 (m 1 H), 4.38 (q, J=7.1 Hz, 2 H), 8.01 (s, 1 H).

EXAMPLE 5(36)(13E)-17-oxa-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.16 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.70 (dt, J=15.3, 6.6 Hz, 1H), 5.33 (dd,J=15.3, 8.7 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.15 (m, 1H), 3.82 (m, 1H),3.50-3.27 (m, 7H), 2.47-2.12 (m, 5H), 1.73 (m, 1H), 1.39 (t, J=7.2 Hz,3H), 1.17 (t, J=7.2 Hz, 3H).

EXAMPLE 5(37)(13E)-16-oxa-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.17 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.02 (s, 1H), 5.79 (dt, J=15.3, 5.1 Hz, 1H), 5.53 (ddt,J=15.3, 8.4, 1.8 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 4.24 (m, 1H), 3.92(dd, J=5.1, 1.8 Hz, 2(m, 1H), 3.50-3.41 (m, 2H), 3.40-3.24 (m, 3H),2.49-2.14 (m, 3H), 1.77 (m, 1H), 1.65-1.51 (m, 2H), 1.39 (t, J=7.2 Hz,3H), 0.90 (t, J=7.2 Hz, 3H).

EXAMPLE 5(38)13-(N-(benzylsulfonyl)amino)-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecanor-5-thia-8-azaprostane

TLC: Rf 0.32 (ethyl acetate);

NMR (CDCl₃): δ 0.97 (t, J=7.20 Hz, 3 H) 1.45 (m, 2 H) 1.73 (m, 2 H) 1.90(m, 1 H) 2.10 (m, 1 H) 2.33 (m, 2 H) 3.02 (m, 1 H) 3.16 (m, 1 H) 3.29(m, 1 H) 3.50 (m, 2 H) 3.82 (m, 2 H) 4.28 (m, 4 H) 5.67 (t, J=6.50 Hz, 1H) 7.30 (m, 3 H) 7.42 (m, 2 H) 8.01 (s, 1 H).

EXAMPLE 5(39)(13E)-19-phenyl-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.41 (hexane:ethyl acetate=1:2);

NMR (CDCl₃): δ 8.01 (s, 1H), 5.64 (dt, J=15.6, 6.6 Hz, 1H), 5.20 (dd,J=15.6, 8.7 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.13 (m, 1H), 3.81 (m, 1H),3.48-3.38 (m, 2H), 3.27 (m, 1H), 2.58 (t, J=7.5 Hz, 2H), 2.4 6-2.11 (m,3H), 2.04-1.93 (m, 2H), 1.69 (m, 1H), 1.64-1.52 (m, 2H), 1.38 (t, J=7.2Hz, 3H), 1.40-1.22 (m, 4H).

EXAMPLE 5(40) 5-(4-ethoxycarbonylthiazol-2-yl)-9,13-dioxo-1,2,3,4,20-pentanor-5-thia-8,14-diazaprostane

TLC: Rf 0.19 (ethyl acetate);

NMR (CDCl₃): δ 8.02 (s, 1H), 7.32 (m, 1H), 4.45-4.34 (m, 3H), 3.88 (m,1H), 3.48-3.30 (m, 3H), 3.29-3.11 (m, 2H), 2.74 (dt, J=16.2,7.8 Hz, 1H),2.39-2.10 (m, 3H), 1.48-1.34 (m, 5H), 1.31-1.10 (m, 4H), 0.81 (t, J=6.9Hz, 3H).

EXAMPLE 5(41)(13E)-16-hydroxy-5-(4-ethoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.28(ethyl acetate);

NMR (CDCl₃): δ 0.91 (m, 3 H), 1.36 (m, 7 H), 1.74 (m, 1 H), 2.25 (m, 5H), 3.58 (m, 6 H), 4.18 (m, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 5.37 (m, 1H), 5.80 (m, 1 H), 8.01 (m, 1 H).

EXAMPLE 5(42)13-(N-methyl-N-(benzylsulfonyl)amino)-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecanor-5-thia-8-azaprostane

TLC: Rf 0.55 (ethyl acetate);

NMR (CDCl₃):δ 0.96 (t, J=7.28 Hz, 3 H) 1.44 (m, 2 H) 1.73 (m, 2 H) 2.03(m, 2 H) 2.25 (m, 1 H) 2.42 (m, 1 H) 2.86 (s, 3 H) 2.95 (dd, J=13.87,8.10 Hz, 1 H) 3.20 (dd, J=14.01, 4.12 Hz, 1 H) 3.29 (m, 1H) 3.42 (m, 2H) 3.82 (m, 2 H) 4.30 (m, 4 H) 7.38 (m, 5 H) 8.01 (s, 1H).

EXAMPLE 5(43)14-oxa-14-(pyridin-3-yl)-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.47(ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ 0.97 (t, J=7.40 Hz, 3 H) 1.46 (m, 2 H) 1.74 (m, 2 H) 2.07(m, 1 H) 2.32 (m, 2 H) 2.60 (m, 1 H) 3.34 (m, 1 H) 3.49 (m, 1 H) 3.61(m, 1 H) 3.89 (m, 1 H) 4.13 (m, 2 H) 4.32 (m, 2 H) 4.59 (dd, J=10.16,3.30 Hz, 1 H) 7.18 (ddd, J=8.40, 4.40, 0.60 Hz, 1 H) 7.26 (ddd, J=8.40,2.90, 1.40 Hz, 1 H) 7.97 (s, 1 H) 8.22 (dd, J=4.40, 1.40 Hz, 1 H) 8.32(m, 1 H).

EXAMPLE 5(44)(13E,15α)-19-phenoxy-15-hydroxy-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

NMR (CDCl₃): δ 7.98 (s, 1H), 7.25 (m, 2H), 6.90 (m, 3H), 5.81 (dd,J=15.0, 5.7 Hz, 1H), 5.58 (dd, J=15.0, 8.4 Hz, 1H), 4.32 (t, J=7.2 Hz,2H), 4.18 (m, 2H), 3.93 (t, J=7.2 Hz, 2H), 3.67 (m, 1H), 3.42 (m, 3H),2.31 (m, 3H), 2.12 (d, J=5.1 Hz, 1H), 1.78 (m, 5H), 1.50 (m, 6H), 0.96(t, J=7.2 Hz, 3H).

EXAMPLE 5(45)(13E,15α)-20-phenoxy-15-hydroxy-5-(4-butoxycarbonylthiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

NMR (CDCl₃): δ 7.99 (s, 1H), 7.25 (m, 2H), 6.90 (m, 3H), 5.82 (dd,J=15.0, 5.7 Hz, 1H), 5.58 (dd, J=15.0, 8.4 Hz, 1H), 4.32 (t, J=7.2 Hz,2H), 4.18 (m, 2H), 3.95 (t, J=7.2 Hz, 2H), 3.67 (m, 1H), 3.42 (m, 3H),2.31 (m, 3H), 2.04 (d, J=5.1 Hz, 1H), 1.78 (m, 5H), 1.50 (m, 8H), 0.96(t, J=7.2 Hz, 3H).

EXAMPLE 6(1) TO 6(92)

By the same procedure as described in Example 2, using the compoundprepared in Example 5(1) to 5(45) or a corresponding ester instead ofthe compound prepared in Example 1, the following compounds of thepresent invention were obtained.

EXAMPLE 6(1)(13E,16α)-17,17-propano-16-hydroxy-5-(4-carboxyoxazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-8-azaprost-13-ene

TLC: Rf 0.10 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.21 (s, 1H), 5.82 (dt, J=15.3, 7.2 Hz, 1H), 5.42 (dd,J=15.3, 9.0 Hz, 1H), 4.06 (m, 1H), 3.64 (dd, J=9.6, 2.1 Hz, 1H), 3.49(dt, J=14.1, 7.2 Hz, 1H), 3.16 (ddd, J=14.1, 8.1, 6.0 Hz, 1H), 2.83 (t,J=7.5 Hz, 2H), 2.52-2.16 (m, 4H), 2.15-1.90 (m, 5H), 1.90-1.56 (m, 6H),1.44 (m, 1H), 0.92 (t, J=7.5 Hz, 3H).

EXAMPLE 6(2)5-(4-carboxythiazol-2-yl)-9-oxo-14,15-(1,4-interphenylene)-1,2,3,4-tetranor-5-thia-8-azaprostane

TLC: Rf 0.55 (methylene chloride:methanol=5:1);

NMR (CDCl₃): δ 8.07 (s, 1H), 7.16-7.01 (m, 4H), 3.98-3.83 (m, 1H),3.73-3.62 (m, 1H), 3.50-3.19 (m, 4H), 2.71-2.01 (m, 8H), 1.82-1.51 (m,4H), 1.39-1.18 (m, 6H), 0.93-0.78 (m, 3H).

EXAMPLE 6(3)(13E)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,18,19,20-heptanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.42 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.09 (s, 1H), 5.71 (dt, J=15.3, 6.9 Hz, 1H), 5.27 (dd,J=15.3, 8.7 Hz, 1H), 4.07 (m, 1H), 3.82 (ddd, J=15.3, 9.0, 5.7 Hz, 1H),3.50 (ddd, J=15.3, 9.6, 5.7 Hz, 1H), 3.41-3.22 (m, 2H), 2.55-2.17 (m,3H), 2.17-1.98 (m, 2H), 1.75 (m, 1H), 1.41 (q, J=7.5 Hz, 2H), 0.90 (t,J=7.5 Hz, 3H).

EXAMPLE 6(4) (13E)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.39 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.09 (s, 1H), 5.72 (dt, J=15.3, 6.6 Hz, 1H), 5.27 (dd,J=15.3, 9.0 Hz, 1H), 4.06 (m, 1H), 3.81 (ddd, J=15.3, 9.6, 6.3 Hz, 1H),3.50 (ddd, J=15.3, 9.6, 5.7 Hz, 1H), 3.42-3.22 (m, 2H), 2.44-2.25 (m,3H), 2.25-2.01 (m, 2H), 1.75 (m, 1H), 1.44-1.32 (m, 4H), 0.90 (t, J=6.9Hz, 3H).

EXAMPLE 6(5)(13E,16α)-17,17-propano-16-hydroxy-3,6-(1,4-interphenylene)-9-oxo-4,5,20-trinor-3-oxa-8-azaprost-13-enoicacid

TLC: Rf 0.30 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 0.92 (t, J=7.5 Hz, 3H), 1.43 (m, 1H), 1.55-2.50 (m, 13H),2.65-2.85 (m, 2H), 3.10 (m, 1H), 3.57 (dd, J=9.6, 2.7 Hz, 1H), 3.65-3.80(m, 2H), 4.00-5.00 (br, 2H), 4.63 (s, 2H), 5.20 (dd, J=15.0, 9.0 Hz,1H), 5.60 (dt, J=15.0, 7.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 2H), 7.09 (d,J=8.2 Hz, 2H).

EXAMPLE 6(6)(2E,13E,16α)-17,17-propano-16-hydroxy-3,6-(1,4-interphenylene)-9-oxo-4,5,20-trinor-8-azaprost-2,13-dienoicacid

TLC: Rf 0.48 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 0.93 (t, J=7.5 Hz, 3H), 1.44 (m, 1H), 1.55-2.50 (m, 13H),2.75-2.95 (m, 2H), 3.18 (m, 1H), 3.57 (dd, J=9.6, 2.4 Hz, 1H), 3.70-3.90(m, 2H), 5.29 (dd, J=15.3, 8.7 Hz, 1H), 5.6 8 (dt, J=15.3, 7.5 Hz, 1H),6.41 (d, J=15.9 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz, 2H),7.73 (d, J=15.9 Hz, 1H).

EXAMPLE 6(7) (13E,16α)-17,17-propano-16-hydroxy-1,7-(2,5-interthienylene)-9-oxo-2,3,4,5,6,20-hexanor-8-azaprost-13-enoicacid

TLC: Rf 0.42 (chloroform:methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 0.93 (t, J=7.5 Hz, 3H), 1.44 (m, 1H), 1.55-2.60 (m, 13H),3.00-4.50 (br, 2H), 3.57 (dd, J=9.9, 2.1 Hz, 1H), 4.02 (m, 1H), 4.20 (d,J=15.0 Hz, 1H), 4.94 (d, J=15.0 Hz, 1H), 5.37 (dd, J=15.3, 9.3 Hz, 1H),5.80 (dt, J=15.3, 7.5 Hz, 1H), 6.95 (d, J=3.0 Hz, 1H), 7.68 (d, J=3.0Hz, 1H).

EXAMPLE 6(8)(13E)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.30 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 5.72 (dt, J=15.0, 6.9 Hz, 1H), 5.26 (dd,J=15.0, 8.7 Hz, 1H), 4.06 (m, 1H), 3.81 (ddd, J=13.5, 9.6, 6.0 Hz, 1H),3.50 (ddd, J=13.5, 9.6, 5.1 Hz, 1H), 3.40-3.21 (m, 2H), 2.55-2.14 (m,3H), 2.12-1.99 (m, 2H), 1.75 (m, 1H), 1.45-1.20 (m, 8H), 0.88 (t, J=6.9Hz, 3H).

EXAMPLE 6(9)(13E)-5-(4-carboxythiazol-2-yl)-9-oxo-20-methyl-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.30 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.09 (s, 1H), 5.71 (dt, J=15.3, 6.6 Hz, 1H), 5.26 (dd,J=15.3, 8.7 Hz, 1H), 4.06 (m, 1H), 3.81 (ddd, J=13.5, 9.6, 5.7 Hz, 1H),3.49 (ddd, J=13.5, 9.6, 5.7 Hz, 1H), 3.42-3.20 (m, 2H), 2.54-2.15 (m,3H), 2.14-1.99 (m, 2H), 1.75 (m, 1H), 1.45-1.17 (m, 10H), 0.88 (t, J=6.9Hz, 3H).

EXAMPLE 6(10)(13E,15α)-15-hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.51 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (d6-dmso): δ 7.84 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 5.62(dd, J=15.6, 6.3 Hz, 1H), 5.33 (dd, J=15.6, 8.7 Hz, 1H), 4.71 (d, J=4.8Hz, 1H), 4.00-3.84 (m, 2H), 3.60 (m, 1H), 2.99 (m, 1H), 2.89-2.66 (m,2H), 2.30-2.00 (m, 3H), 1.60 (m, 1H), 1.50-1.15 (m, 8H), 0.81 (t, J=6.3Hz, 3H).

EXAMPLE 6(11)(13E,15α)-15-hydroxy-1,5-(2,5-interthienylene)-9-oxo-2,3,4-trinor-8-azaprost-13-enoicacid

TLC: Rf 0.44 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 7.69 (d, J=3.9 Hz, 1H), 6.83 (d, J=3.9 Hz, 1H), 5.69 (dd,J=15.3, 6.0 Hz, 1H), 5.49 (ddd, J=15.3, 8.4, 1.0 Hz, 1H), 4.20-3.99 (m,2H), 3.60 (m, 1H), 3.00 (m, 1H), 2.85 (t, J=7.8 Hz, 2H), 2.52-2.17 (m,3H), 2.00-1.70 (m, 3H), 1.61-1.20 (m, 8H), 0.89 (t, J=6.3 Hz, 3H).

EXAMPLE 6(12) (13E,15α)-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic acid

TLC: Rf 0.49 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 5.73 (dd, J=15.3, 5.7 Hz, 1H), 5.53 (ddd, J=15.3, 8.4,1.2 Hz, 1H), 4.18 (m, 2H), 3.63 (m, 1H), 3.11 (m, 1H), 2.78-2.20 (m,9H), 2.00-1.70 (m, 3H), 1.62-1.21 (m, 8H), 0.90 (t, J=6.6 Hz, 3H).

EXAMPLE 6(13)5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprostane

TLC: Rf 0.37 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.09 (s, 1H), 3.94 (ddd, J=13.2, 9.3, 5.1 Hz, 1H), 3.65(m, 1H), 3.54-3.25 (m, 3H), 2.52-2.28 (m, 2H), 2.16 (m, 1H), 1.82-1.62(m, 2H), 1.46-1.02 (m, 11H), 0.88 (t, J=6.9 Hz, 3H).

EXAMPLE 6(14) (13E,15α)-20-ethyl-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.10 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.10 (s, 1H), 5.79 (dd, J=15.3, 5.7 Hz, 1H), 5.55 (dd,J=15.3, 8.7 Hz, 1H), 4.21-4.11 (m, 2H), 4.0-3.1 (br), 3.90-3.75 (m, 1H),3.55-3.30 (m, 3H), 2.56-2.20 (m, 3H), 1.86-1.72 (m, 1H), 1.62-1.42 (m,2H), 1.42-1.20 (m, 10H), 0.90 (t, J=7.2 Hz, 3H).

EXAMPLE 6(15)(13E,15α)-20-methyl-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.20 (methylene chloride:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 8.09 (s, 1H), 5.79 (dd, J=15.6, 6.0 Hz, 1H), 5.53 (dd,J=15.6, 9.0 Hz, 1H), 4.20-4.10 (m, 2H), 3.90-3.70 (m, 1H), 3.50-3.30 (m,3H), 2.50-2.20 (m, 3H), 1.85-1.70 (m, 1H), 1.60-1.40 (m, 2H), 1.40-1.15(m, 8H), 0.95-0.80 (m, 3H).

EXAMPLE 6(16)(13E,15α)-20-n-propyl-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.23(methylene chloride: methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 8.09 (s, 1H), 5.79 (dd, J=15.3, 6.0 Hz, 1H), 5.53 (dd,J=15.3, 8.4 Hz, 1H), 4.20-4.10 (m, 2H), 3.90-3.70 (m, 1H), 3.50-3.30 (m,3H), 2.50-2.20 (m, 3H), 1.85-1.70 (m, 1H), 1.60-1.40 (m, 2H), 1.40-1.15(m, 12H), 0.90-0.80 (m, 3H).

EXAMPLE 6(17)(13Z)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 5.67 (dt, J=10.8, 7.8 Hz, 1H), 5.25 (dd,J=10.8, 9.6 Hz, 1H), 4.49 (dt, J=9.6, 7.2 Hz, 1H), 3.76 (m,1H), 3.51 (m,1H), 3.42-3.23 (m, 2H), 2.54-2.32 (m, 2H), 2.22 (m, 1H), 2.17-2.01 (m,2H), 1.71 (m, 1H), 1.45-1.20 (m, 6H), 0.90 (t, J=6.6 Hz, 3H).

EXAMPLE 6(18)(13Z)-16-oxa-17,17-dimethyl-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.30 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 5.84 (dt, J=10.8, 7.2 Hz, 1H), 5.41 (ddt,J=10.8, 9.9, 1.5 Hz, 1H), 4.62 (dt, J=9.9, 7.2 Hz, 1H), 4.07 (ddd,J=11.7, 7.2, 1.5 Hz, 1H), 3.94 (ddd, J=11.7, 7.2, 1.5 Hz, 1H), 3.82 (m,1H), 3.60-3.38 (m, 2H), 3.24 (m, 1H), 2.56-2.18 (m, 3H), 1.74 (m, 1H),1.23 (s, 9H).

EXAMPLE 6(19)(13E)-16-oxa-17,17-dimethyl-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.28 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 5.83 (dt, J=15.3, 5.1 Hz, 1H), 5.55 (ddt,J=15.3, 9.0, 1.5 Hz, 1H), 4.14 (m, 1H), 3.93 (dd, J=5.1, 1.5 Hz, 2H),3.83 (dt, J=13.8, 7.8 Hz, 1H), 3.50 (dt, J=13.8, 7.8 Hz, 1H), 3.32 (t,J=7.8 Hz, 2H), 2.55-2.17 (m, 3H), 1.79 (m, 1H), 1.21 (s, 9H).

EXAMPLE 6(20)(13E,15α)-19-phenyl-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.09 (s, 1H), 7.36-7.10 (m, 5H), 5.79 (dd, J=15.0, 5.7Hz, 1H), 5.60-5.15 (m, 1H), 4.22-4.10 (m, 2H), 3.80 (m, 1H), 3.47-3.28(m, 3H), 2.64-2.18 (m, 5H), 1.82-1.23 (m, 7H).

EXAMPLE 6(21)(13E,15α)-20-phenyl-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.09 (s, 1H), 7.36-7.12 (m, 5H), 5.78 (dd, J=15.3, 5.7Hz, 1H), 5.54 (dd, J=15.3, 8.7 Hz, 1H), 4.20-4.10 (m, 2H), 3.81 (m, 1H),3.55-3.27 (m, 3H), 2.65-2.20 (m, 5H), 1.85-1.23 (m, 9H).

EXAMPLE 6(22)(13E,15α)-20-benzyl-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.35 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.09 (s, 1H), 7.37-7.12 (m, 5H), 5.78 (dd, J=15.3, 6.0Hz, 1H), 5.55 (ddd, J=15.3, 8.7, 1.2 Hz, 1H), 4.20-4.08 (m, 2H), 3.81(m, 1H), 3.55-3.27 (m, 3H), 2.64-2.20 (m, 5H), 1.86-1.21 (m, 11H).

EXAMPLE 6(23)(13E,16α)-17,17-propano-16-hydroxy-1,6-(1,3-interphenylene)-9-oxo-2,3,4,5,20-pentanor-8-azaprost-13-enoicacid

TLC: Rf 0.41 (ethyl acetate:acetic acid=100:1);

NMR (CDCl₃): δ 0.92 (t, J=7.5 Hz, 2H), 1.44 (m, 1H), 1.55-2.50 (m, 13H),2.75-3.00 (m, 2H), 3.20 (m, 1H), 3.59 (dd, J=9.9, 2.4 Hz, 1H), 3.70-3.90(m, 2H), 5.28 (dd, J=15.0, 9.0 Hz, 1H), 5.79 (dt, J=15.0, 7.2 Hz, 1H),7.39 (t, J=7.5 Hz, 1H), 7.46 (m, 1H), 7.92-8.00 (m, 2H).

EXAMPLE 6(24)(15α)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprostane

TLC: Rf 0.49 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 3.95-3.23 (m, 6H), 2.55-2.06 (m, 3H), 1.94(m, 1H), 1.78-1.60 (m, 2H), 1.59-1.00 (m, 10H), 0.89 (t, J=6.6 Hz, 3H).

EXAMPLE 6(25)(15α)-15-hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-5-thia-8-azaprostanoicacid

TLC: Rf 0.21 (chloroform:methanol=9:1);

NMR (CDCl₃—CD₃OD): δ 7.97 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H),3.82 (m, 1H), 3.60-3.30 (m, 3H), 3.20 (m, 1H), 3.01-2.80 (m, 2H),2.45-2.21 (m, 2H), 2.08 (m, 1H), 1.80-1.20 (m, 13H), 0.89 (t, J=6.6 Hz,3H).

EXAMPLE 6(26)(13E)-17,17-dimethyl-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 5.73 (dt, J=15.3, 6.6 Hz, 1H), 5.27 (dd,J=15.3, 9.0 Hz, 1H), 4.05 (m, 1H), 3.83 (ddd, J=13.5, 9.0, 6.3 Hz, 1H),3.49 (ddd, J=13.5, 9.6, 6.0 Hz, 1H), 3.39-3.21 (m, 2H), 2.54-2.15 (m,3H), 2.09-1.97 (m, 2H), 1.75 (m, 1H), 1.30-1.20 (m, 2H), 0.89 (s, 9H).

EXAMPLE 6(27)(13E)-17,17-dimethyl-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.35 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.09 (s, 1H), 5.72 (dt, J=15.0, 6.9 Hz, 1H), 5.26 (dd,J=15.0, 8.7 Hz, 1H), 4.05 (m, 1H), 3.82 (ddd, J=13.5, 9.0, 6.9 Hz, 1H),3.49 (ddd, J=13.5, 9.9, 6.0 Hz, 1H), 3.40-3.24 (m, 2H), 2.54-2.15 (m,3H), 2.10-1.93 (m, 2H), 1.75 (m, 1H), 1.29-1.16 (m, 4H), 0.98-0.75 (m,9H).

EXAMPLE 6(28)(13E,15α)-19-phenyl-15-hydroxy-9-oxo-20-nor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.24 (methylene chloride:methanl=9:1);

NMR (CDCl₃): δ 7.30-7.23 (m, 2H), 7.21-7.14 (m, 3H), 5.71 (dd, J=15.3,5.7 Hz, 1H), 5.50 (dd, J=15.3, 8.4 Hz, 1H), 4.20-4.06 (m, 2H), 3.72-3.58(m, 1H), 3.14-3.00 (m, 1H), 2.70-2.16 (m, 11H), 1.96-1.82 (m, 2H),1.80-1.20 (m, 7H).

EXAMPLE 6(29)(13E,15α)-20-phenyl-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic acid

TLC: Rf 0.24 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.30-7.23 (m, 2H), 7.21-7.14 (m, 3H), 5.72 (dd, J=15.3,5.7 Hz, 1H), 5.51 (dd, J=15.3, 8.1 Hz, 1H), 4.20-4.06 (m, 2H), 3.72-3.58(m, 1H), 3.16-3.04 (m, 1H), 2.72-2.16 (m, 11H), 1.96-1.82 (m, 2H),1.80-1.24 (m, 9H).

EXAMPLE 6(30)(13E,15α)-20-benzyl-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic acid

TLC: Rf 0.24 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.30-7.23 (m, 2H), 7.21-7.14 (m, 3H), 5.73 (dd, J=15.3,5.4 Hz, 1H), 5.51 (ddd, J=15.3, 8.1, 0.9 Hz, 1H), 4.20-4.06 (m, 2H),3.72-3.60 (m, 1H), 3.16-3.04 (m, 1H), 2.72-2.16 (m, 11H), 1.96-1.84 (m,2H), 1.80-1.20 (m, 11H).

EXAMPLE 6(31) 14-oxa-14-phenyl-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.35 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.29 (dd, J=8.4, 7.5 Hz, 2H), 6.98 (t,J=7.5 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 4.20 (dd, J=9.9, 3.6 Hz, 1H),4.09 (m, 1H), 3.99 (dd, J=9.9, 5.4 Hz, 1H), 3.91 (m, 1H), 3.75 (m , 1H),3.51 (m, 1H), 3.29 (m, 1H), 2.60 (m, 1H), 2.43 (m, 1H), 2.25 (m, 1H),1.96 (m, 1H).

EXAMPLE 6(32)14-oxa-14-(3,5-dichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.41 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃):68.11 (s, 1H), 6.98 (t, J=1.8 Hz, 1H), 6.82 (d, J=1.8Hz,2H), 4.31 (dd, J=9.9, 3.0 Hz, 1H), 4.08 (m, 1H), 3.98 (dd, J=9.9, 3.0Hz, 1H), 3.90 (m, 1H), 3.68 (m, 1H), 3.48 (m, 1H), 3.28 (m, 1H ), 2.59(m, 1H), 2.43 (m, 1H), 2.25 (m, 1H), 1.97 (m, 1H).

EXAMPLE 6(33)(13E,16)-17,17-propano-16-hydroxy-6-(4-carboxythiazol-2-ylsulfonyl)-9-oxo-1,2,3,4,5,20-hexanor-8-azaprost-13-ene

TLC: Rf 0.14 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 0.93 (t, J=7.5 Hz, 3 H), 1.44 (m, 1 H), 1.55-2.20 (m, 10H), 2.20-2.55 (m, 4 H), 3.60-4.00 (m, 5 H), 4.00-4.40 (m, 2 H), 5.41(dd, J=15.3, 9.0 Hz, 1 H), 5.96 (dt, J=15.3, 7.2 Hz, 1 H), 8.54 (s, 1H).

EXAMPLE 6(34)14-oxa-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,19,20-hexanor-5-thia-8-azaprostane

TLC: Rf 0.25 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 3.96-3.69 (m, 3H), 3.58-3.38 (m, 5H), 3.29(m, 1H), 2.56-2.29 (m, 2H), 2.12 (m, 1H), 1.75 (m, 1H), 1.60-1.48 (m,2H), 1.42-1.24 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

EXAMPLE 6(35) 17,17-propano-5-(4-carboxythiazol-2-yl)-9,16-dioxo-1,2,3,4,20-pentanor-5-thia-8-azaprostane

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 0.75 (t, J=7.5 Hz, 3 H), 1.30-2.00 (m, 11 H), 2.10-2.55(m, 7 H), 3.25-3.55 (m, 3 H), 3.67 (m, 1 H), 3.95 (m, 1 H), 8.09 (s, 1H).

EXAMPLE 6(36)(13E)-17-oxa-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 5.77 (dt, J=15.3, 6.9 Hz, 1H), 5.37 (dd,J=15.3, 8.7 Hz, 1H), 4.07 (m, 1H), 3.76 (m, 1H), 3.63-3.42 (m, 5H),3.38-3.28 (m, 2H), 2.55-2.17 (m, 5H), 1.76 (m, 1H), 1.20 (t, J=7.2 Hz,3H).

EXAMPLE 6(37)(13E)-16-oxa-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.36 (chloroform:methanol:acetic acid=9:1:0.1); NMR (CDCl₃): δ8.09 (s, 1H), 5.83 (dt, J=15.3, 5.4 Hz, 1H), 5.57 (ddt, J=15.3, 8.7, 1.2Hz, 1H), 4.15 (m, 1H), 3.98 (dd, J=5.4, 1.2 Hz, 2H), 3.85 (m, 1H),3.55-3.26 (m, 5H), 2.55-2.17 (m, 3H), 1.79 (m, 1H), 1.68-1.53 (m, 2H),0.92 (t, J=7.2

EXAMPLE 6(38)13-(N-(phenylsulfonyl)amino)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecanor-5-thia-8-azaprostane

TLC: Rf 0.22 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 2.00-2.25 (m, 2 H), 2.38 (m, 1 H), 2.60 (m, 1 H),3.00-3.42 (m, 5 H), 3.90-4.02 (m, 2 H), 6.19 (t, J=6.6 Hz, 1 H),7.45-7.60 (m, 3 H), 7.86 (m, 2 H), 8.09 (s, 1 H).

EXAMPLE 6(39)13-(N-(benzylsulfonyl)amino)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecanor-5-thia-8-azaprostane

TLC: Rf 0.27 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 1.90-2.18 (m, 2 H), 2.31 (m, 1 H), 2.51 (m, 1 H),2.95-3.40 (m, 5 H), 3.76 (m, 1 H), 3.91 (m, 1 H), 4.31 (s, 2 H), 5.72(t, J=6.6 Hz, 1 H), 7.30-7.40 (m, 3 H), 7.40-7.45 (m, 2 H), 8.12 (s, 1H).

EXAMPLE 6(40)(13E)-19-phenyl-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.43 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.36-7.23 (m, 2H), 7.22-7.14 (m, 3H), 5.69(dt, J=15.0, 6.6 Hz, 1H), 5.25 (dd, J=15.0, 8.7 Hz, 1H), 4.04 (m, 1H),3.80 (m, 1H), 3.48 (m, 1H), 3.38-3.18 (m, 2H), 2.61 (t, J=7.5 Hz, 2H),2.53-2.29 (m, 2H), 2.21 (m, 1H), 2.13-1.98 (m, 2H), 1.73 (m, 1H),1.68-1.54 (m, 2H), 1.48-1.34 (m, 4H).

EXAMPLE 6(41)5-(4-carboxythiazol-2-yl)-9,13-dioxo-1,2,3,4,20-pentanor-5-thia-8,14-diazaprostane

TLC: Rf 0.17 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.11 (s, 1H), 7.16 (t, J=5.4 Hz, 1H), 4.41 (dd, J=8.4,3.6 Hz, 1H), 3.90 (m, 1H), 3.53-3.23 (m, 5H), 2.72 (m, 1H), 2.47-2.03(m, 3H), 1.52-1.35 (m, 2H), 1.34-1.10 (m, 4H), 0.82 (t, J=6.9 Hz, 3H).

EXAMPLE 6(42)(13E)-16-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.28 (chloroform: methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 0.92 (t, J=6.30 Hz, 3 H) 1.41 (m, 4 H) 1.74 (m, 1 H) 2.30(m, 5 H), 3.52 (m, 5 H) 4.10 (m, 1 H) 4.52 (br. s., 2 H) 5.37 (m, 1 H)5.82 (m, 1 H) 8.07 (s, 1 H).

EXAMPLE 6(43)13-(N-methyl-N-(benzylsulfonyl)amino)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,14,15,16,17,18,19,20-undecanor-5-thia-8-azaprostane

TLC: Rf 0.33 (chloroform: methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 1.89 (m, 1 H) 2.06 (m, 1 H) 2.29 (m, 1 H) 2.44 (m, 1 H)2.76 (dd, J=14.30, 7.80 Hz, 1 H) 2.85 (s, 3 H) 3.02 (dd, J=14.30, 4.40Hz, 1 H) 3.20 (m, 1 H) 3.34 (m, 2 H) 3.72 (m, 1 H) 3.90 (m, 1 H) 4.30(s, 2 H) 7.39 (s, 5 H) 8.10 (s, 1 H).

EXAMPLE 6(44)14-oxa-14-(pyridin-3-yl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.32 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.09 (m, 1 H) 2.26 (m, 1 H) 2.43 (ddd, J=16.80, 9.90,5.70 Hz, 1 H) 2.62 (ddd, J=16.80, 10.00, 6.90 Hz, 1 H) 3.23 (m, 1 H)3.47 (m, 1 H) 3.68 (m, 1 H) 3.84 (m, 1 H) 4.17 (m, 2 H) 4.88 (m, 1 H)6.64 (br. s., 1 H) 7.31 (m, 2 H) 8.03 (s, 1 H) 8.22 (m, 1H) 8.58 (m,1H).

EXAMPLE 6(45) 14-oxa-14-(2,5-dichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.44 (chloroform: methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.29 (m, 1 H) 2.45 (m, 1 H) 2.68 (m, 1 H)3.28 (m, 1 H) 3.55 (m, 1 H) 3.81 (m, 1 H) 3.99 (m, 2 H) 4.15 (m, 1 H)4.30 (dd, J=9.89, 2.47 Hz, 1 H) 6.93 (m, 2 H) 7.29 (d, J=9.60 Hz, 1H)8.08 (s, 1H).

EXAMPLE 6(46)14-oxa-14-(2,4,5-trichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.44 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.96 (m, 1 H) 2.37 (m, 2 H) 2.69 (m, 1 H) 3.27 (m, 1 H)3.53 (m, 1 H) 3.77 (m, 1 H) 3.97 (m, 2 H) 4.13 (m, 1 H) 4.37 (dd,J=9.89, 2.47 Hz, 1 H) 7.07 (s, 1 H) 7.46 (s, 1 H) 8.09 (s, 1 H).

EXAMPLE 6(47)14-oxa-14-(3,4-dichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.40 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.26 (m, 1 H) 2.43 (m, 1 H) 2.59 (m, 1 H)3.28 (m, 1 H) 3.48 (m, 1 H) 3.70 (m, 1 H) 3.94 (m, 2 H) 4.08 (m, 1 H)4.25 (m, 1 H) 6.76 (dd, J=8.80, 2.70 Hz, 1 H) 7.02 (d, J=2.70 Hz, 1 H)7.33 (d, J=8.80 Hz, 1 H) 8.10 (s, 1 H).

EXAMPLE 6(48)14-oxa-14-(2,3,4,5,6-pentafluorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.38 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.01 (m, 1 H) 2.28 (m, 1 H) 2.43 (m, 1 H) 2.59 (m, 1 H)3.39 (m, 1 H) 3.52 (m, 1 H) 3.70 (m, 1 H) 4.10 (m, 3 H) 4.38 (dd,J=9.90, 3.00 Hz, 1 H) 8.10 (s, 1 H).

EXAMPLE 6(49)14-oxa-14-(3,4-difluorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.36 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.26 (m, 1 H) 2.43 (m, 1 H) 2.59 (m, 1 H)3.29 (m, 1 H) 3.48 (m, 1 H) 3.71 (m, 1 H) 3.94 (m, 2 H) 4.07 (m, 1 H)4.18 (m, 1 H) 6.59 (m, 1 H) 6.73 (m, 1 H) 7.07 (m, 1 H) 8.10 (s, 1 H).

EXAMPLE 6(50)14-oxa-14-(2-nitro-3-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.33 (chloroform: methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 1.84 (m, 1 H) 2.32 (m, 1 H) 2.32 (s, 3 H) 2.48 (m, 2 H)3.27 (m, 1 H) 3.45 (m, 1 H) 3.69 (m, 1 H) 3.96 (m, 1 H) 4.10 (m, 2 H)4.23 (m, 1 H) 6.87 (d, J=8.10 Hz, 1 H) 6.92 (d, J=8.10 Hz, 1 H) 7.32 (t,J=8.10 Hz, 1 H) 8.07 (s, 1 H).

EXAMPLE 6(51)14-oxa-14-(3-chloro-4-formylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.56 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.00 (m, 1 H) 2.29 (m, 1 H) 2.45 (m, 1 H) 2.61 (m, 1 H)3.29 (m, 1 H) 3.48 (m, 1 H) 3.69 (m, 1 H) 3.94 (m, 1 H) 4.12 (m, 2 H)4.40 (m, 1 H) 6.91 (m, 1 H) 6.98 (d, J=2.20 Hz, 1 H) 7.90 (d, J=8.79 Hz,1 H) 8.10 (s, 1 H) 10.32 (s, 1 H).

EXAMPLE 6(52)14-oxa-14-(4-nitro-3-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.51 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.00 (m, 1 H) 2.29 (m, 1 H) 2.45 (m, 1 H) 2.62 (m, 1 H)2.62 (s, 3 H) 3.29 (m, 1 H) 3.48 (m, 1 H) 3.70 (m, 1 H) 3.94 (m, 1 H)4.11 (m, 2 H) 4.36 (m, 1 H) 6.81 (m, 2 H) 8.07 (m, 1 H) 8.10 (s, 1 H).

EXAMPLE 6(53)14-oxa-14-(3-nitro-2-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.47 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.02 (m, 1 H) 2.33 (m, 1 H) 2.33 (s, 3 H) 2.47 (m, 1 H)2.62 (m, 1 H) 3.29 (m, 1 H) 3.50 (m, 1 H) 3.72 (m, 1 H) 3.96 (m, 1 H)4.14 (m, 2 H) 4.29 (dd, J=9.60, 3.00 Hz, 1 H) 7.07 (d, J=8.20 Hz, 1 H)7.27 (t, J=8.20 Hz, 1 H) 7.44 (m, 1 H) 8.09 (s, 1 H).

EXAMPLE 6(54)14-oxa-14-(4-chloro-3-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.51 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.33 (m, 2 H) 2.33 (s, 3 H) 2.59 (m, 1 H)3.27 (m, 1 H) 3.49 (m, 1 H) 3.74 (m, 1 H) 3.92 (m, 2 H) 4.06 (m, 1 H)4.16 (dd, J=9.60, 3.00 Hz, 1 H) 6.66 (dd, J=8.80, 2.70 Hz, 1 H) 6.76 (d,J=2.70 Hz, 1 H) 7.23 (d, J=8.80 Hz, 1 H) 8.09 (s, 1 H).

EXAMPLE 6(55)14-oxa-14-(3-nitro-4-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.56 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.02 (m, 1 H) 2.35 (m, 2 H) 2.51 (s, 3 H) 2.63 (m, 1 H)3.29 (m, 1 H) 3.49 (m, 1 H) 3.70 (m, 1 H) 3.93 (m, 1 H) 4.10 (m, 2 H)4.41 (dd, J=10.03, 2.88 Hz, 1 H) 5.66 (br. s., 1 H) 7.06 (dd, J=8.38,2.61 Hz, 1 H) 7.24 (d, J=8.52 Hz, 1 H) 7.54 (d, J=2.75 Hz, 1 H) 8.10 (s,1 H).

EXAMPLE 6(56)14-oxa-14-(3-bromophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.46 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.96 (m, 1H) 2.25 (m, 1H) 2.43 (m, 1H) 2.60 (m, 1H) 3.28(ddd, J=13.40, 10.16, 5.36 Hz, 1 H) 3.49 (ddd, J=13.40, 10.16, 5.22 Hz,1 H) 3.72 (m, 1 H) 4.01 (m, 3 H) 4.22 (dd, J=9.89, 3.02 Hz, 1 H) 6.82(td, J=4.60, 2.34 Hz, 1 H) 7.10 (m, 3 H) 8.09 (s, 1 H).

EXAMPLE 6(57)14-oxa-14-(2,3-dimethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.48 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.11 (s, 3 H) 2.27 (s, 3 H) 2.27 (m, 1 H)2.45 (m, 1 H) 2.63 (m, 1 H) 3.26 (ddd, J=13.40, 10.16, 5.49 Hz, 1 H)3.52 (ddd, J=13.40, 10.16, 5.22 Hz, 1 H) 3.88 (m, 3 H) 4.17 (m, 2 H)6.68 (d, J=8.52 Hz, 1 H) 6.81 (d, J=7.69 Hz, 1 H) 7.05 (t, J=7.97 Hz, 1H) 8.08 (s, 1 H).

EXAMPLE 6(58)14-oxa-14-(4-chloro-2,6-dimethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.47 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.34 (m, 2 H) 2.34 (s, 6 H) 2.59 (m, 1 H)3.27 (ddd, J=13.32, 10.03, 5.22 Hz, 1 H) 3.49 (m, 1 H) 3.74 (m, 1 H)3.91 (m, 2 H) 4.12 (m, 2 H) 6.62 (s , 2 H) 8.08 (s, 1 H).

EXAMPLE 6(59)14-oxa-14-(naphthalen-2-yl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.44 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 2.01 (m, 1 H) 2.28 (m, 1 H) 2.45 (m, 1 H) 2.64 (m, 1 H)3.29 (m, 1 H) 3.52 (m, 1 H) 3.80 (m, 1 H) 3.94 (m, 1 H) 4.12 (m, 2 H)4.32 (m, 1 H) 7.12 (m, 2 H) 7.36 (td, J=7.49, 1.24 Hz, 1 H) 7.46 (td,J=7.55, 1.37 Hz, 1 H) 7.75 (m, 3 H) 8.06 (s, 1 H).

EXAMPLE 6(60)14-oxa-14-(2-fluoro-3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.35 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.28 (m, 1 H) 2.44 (m, 1 H) 2.61 (m, 1 H)3.35 (ddd, J=13.40, 10.10, 5.40 Hz, 1 H) 3.52 (ddd, J=13.40, 10.10, 5.40Hz, 1 H) 3.72 (m, 1 H) 4.09 (m , 3 H) 4.33 (dd, J=9.48, 2.88 Hz, 1 H)7.17 (m, 3 H) 8.09 (s, 1 H).

EXAMPLE 6(61)14-oxa-14-(3,5-dimethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.45 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.23 (m, 1 H) 2.28 (s, 6 H) 2.42 (m, 1 H)2.59 (m, 1 H) 3.27 (m, 1 H) 3.51 (m, 1 H) 3.95 (m, 5 H) 6.50 (s, 2 H)6.64 (s, 1 H) 8.08 (s, 1 H).

EXAMPLE 6(62)14-oxa-14-(3,4,5-trimethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.43(chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.92 (m, 1 H) 2.10 (s, 3 H) 2.20 (m, 1 H) 2.25 (s, 6 H)2.42 (m, 1 H) 2.58 (m, 1 H) 3.26 (m, 1 H) 3.51 (m, 1 H) 3.96 (m, 5 H)6.55 (s, 2 H) 8.07 (s, 1 H).

EXAMPLE 6(63)14-oxa-14-(5,6,7,8-tetrahydronaphthalen-1-yl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.42 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.76 (m, 4 H) 1.97 (m, 1 H) 2.27 (m, 1 H) 2.58 (m, 6 H)3.23 (m, 1 H) 3.51 (m, 1 H) 3.96 (m, 5 H) 6.61 (d, J=8.24 Hz, 1 H) 6.74(d, J=7.42 Hz, 1 H) 7.06 (t, J=7 .97 Hz, 1 H) 8.07 (s, 1 H).

EXAMPLE 6(64)14-oxa-14-(4-acetyl-3-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.42 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): 5 1.97 (m, 1 H) 2.45 (m, 3 H) 2.55 (s, 6 H) 3.27 (m, 1 H)3.49 (m, 1 H) 3.74 (m, 1 H) 3.93 (m, 1 H) 4.08 (m, 2 H) 4.24 (m, 1 H)6.74 (m, 2 H) 7.74 (d, J=9.34 Hz, 1 H) 8.08 (s, 1 H).

EXAMPLE 6(65)14-oxa-14-(naphthalen-1-yl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.07 (m, 1 H) 2.35 (m, 1 H) 2.51 (m, 1 H) 2.70 (m, 1 H)3.26 (m, 1 H) 3.55 (m, 1 H) 3.92 (m, 2 H) 4.23 (m, 2 H) 4.36 (m, 1 H)6.82 (m, 1 H) 7.37 (m, 1 H) 7.50 (m, 3 H) 7.82 (m, 1H) 8.03 (s, 1H) 8.09(m, 1H).

EXAMPLE 6(66)14-oxa-14-(2-chloro-3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.42 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.96 (m, 1 H) 2.38 (m, 2 H) 2.69 (m, 1 H) 3.31 (m, 1 H)3.55 (m, 1 H) 3.81 (m, 1 H) 4.11 (m, 3 H) 4.33 (m, 1 H) 7.14 (m, 1 H)7.34 (m, 2 H) 8.08 (s, 1 H).

EXAMPLE 6(67)14-oxa-14-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.49 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.25 (s, 1 H) 2.33 (s, 3 H) 2.43 (m, 1 H)2.60 (m, 1 H) 3.15 (br. s., 1 H) 3.28 (m, 1 H) 3.51 (m, 1 H) 3.76 (m, 1H) 3.94 (m, 2 H) 4.12 (m, 2 H) 6.68 (m, 2 H) 6.81 (m, 1 H) 7.17 (t,J=7.69 Hz, 1 H) 8.08 (s, 1 H).

EXAMPLE 6(68)14-oxa-14-(4-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.47 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.23 (m, 1 H) 2.29 (s, 3 H) 2.42 (ddd,J=16.80, 10.00, 6.00 Hz, 1 H) 2.59 (ddd, J=16.80, 10.00, 6.90 Hz, 1 H)3.28 (ddd, J=13.20, 10.20, 5.40 Hz, 1H) 3.50 (ddd, J=13.20, 10.20, 5.40Hz, 1H) 3.77 (ddd, J=13.20, 10.20, 5.40 Hz, 1 H) 3.93 (m, 2 H) 4.10 (m,2 H) 6.77 (d, J=8.80 Hz, 2 H) 7.09 (d, J=8.80 Hz, 2 H) 8.08 (s, 1H).

EXAMPLE 6(69)14-oxa-14-(2,3,5-trichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.55 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.30 (m, 1 H) 2.45 (m, 1 H) 2.68 (m, 1 H)3.26 (m, 1 H) 3.54 (m, 1 H) 3.78 (m, 1 H) 3.99 (m, 2 H) 4.15 (m, 1 H)4.32 (m, 1 H) 6.88 (d, J=2.20 Hz, 1 H) 7.14 (dd, J=2.20, 0.55 Hz, 1 H)8.08 (s, 1 H).

EXAMPLE 6(70)14-oxa-14-(3-chloro-4-fluorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.52 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.96 (m, 1 H) 2.25 (m, 1 H) 2.43 (m, 1 H) 2.59 (m, 1 H)3.28 (m, 1 H) 3.48 (m, 1 H) 3.70 (m, 1 H) 3.93 (m, 2 H) 4.07 (m, 1 H)4.21 (m, 1 H) 6.75 (dt, J=9.00, 3.00 Hz, 1 H) 6.94 (dd, J=5.70, 3.00 Hz,1 H) 7.05 (t, J=9.00 Hz, 1 H) 8.09 (s, 1 H).

EXAMPLE 6(71)14-oxa-14-(2,3-dichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.41 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.29 (m, 1 H) 2.45 (m, 1 H) 2.67 (m, 1 H)3.29 (m, 1 H) 3.56 (m, 1 H) 3.81 (m, 1 H) 4.12 (m, 4 H) 6.84 (dd,J=7.42, 1.92 Hz, 1 H) 7.14 (m, 2 H) 8.07 (s, 1 H).

EXAMPLE 6(72)14-oxa-14-(3-nitrophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.45 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.04 (m, 1 H) 2.29 (m, 1 H) 2.45 (m, 1 H) 2.63 (m, 1 H)3.30 (m, 1 H) (t, J=8.24 Hz, 1 H) 7.76 (t, J=2.34 Hz, 1 H) 7.85 (m, 1 H)8.09 (s, 1 H).

EXAMPLE 6(73)14-oxa-14-(3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.98 (m, 1 H) 2.27 (m, 1 H) 2.44 (m, 1 H) 2.61 (m, 1 H)3.29 (m, 1 H) 3.49 (m, 1 H) 3.71 (m, 1 H) 4.02 (m, 3 H) 4.30 (dd,J=9.75, 2.88 Hz, 1 H) 7.07 (m, 1 H) 7.13 (br. s., 1 H) 7.25 (m, 1 H)7.41 (t, J=7.97 Hz, 1 H) 8.09 (s, 1 H).

EXAMPLE 6(74)14-oxa-14-(3-trifluoromethoxyphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 1.98 (m, 1 H) 2.26 (m, 1 H) 2.43 (m, 1 H) 2.60 (m, 1 H)3.29 (m, 1 H) 3.49 (m, 1 H) 3.71 (m, 1 H) 4.02 (m, 3 H) 4.24 (dd,J=9.89, 3.02 Hz, 1 H) 6.75 (br. s., 1 H) 6.84 (m, 2 H) 7.30 (t, J=8.24Hz, 1 H) 8.09 (s, 1 H).

EXAMPLE 6(75)14-oxa-14-(2-chloro-4-methoxyphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.92 (m, 1 H) 2.26 (m, 1 H) 2.43 (m, 1 H) 2.65 (m, 1 H)3.31 (m, 1 H) 3.56 (m, 1 H) 3.76 (s, 3 H) 3.80 (m, 2 H) 4.06 (m, 3 H)6.75 (dd, J=9.00, 2.70 Hz, 1 H) 6.85 (d, J=9.00 Hz, 1 H) 6.96 (d, J=2.70Hz, 1 H) 8.07 (s, 1 H).

EXAMPLE 6(76)14-oxa-14-(4-chloro-3-ethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.50 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.21 (t, J=7.50 Hz, 3 H) 1.95 (m, 1 H) 2.25 (m, 1 H) 2.43(m, 1 H) 2.59 (m, 1 H) 2.70 (q, J=7.50 Hz, 2 H) 3.27 (m, 1 H) 3.49 (m, 1H) 3.73 (m, 1 H) 4.03 (m, 4 H) 6.66 (dd, J=8.70, 3.00 Hz, 1 H) 6.76 (d,J=3.00 Hz, 1 H) 7.23 (d, J=8.70 Hz, 1 Hz, 1 H) 8.08 (s, 1 H).

EXAMPLE 6(77)14-oxa-14-(4-methylindan-7-yl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.52 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.91 (m, 1 H) 2.10 (m, 2 H) 2.20 (s, 3 H) 2.24 (m, 1 H)2.42 (m, 1 H) 2.60 (m, 1 H) 2.84 (m, 4 H) 3.25 (m, 1 H) 3.52 (m, 1 H)3.96 (m, 5 H) 6.55 (d, J=8.20 Hz, 1 H) 6.92 (d, J=8.20 Hz, 1 H) 8.07 (s,1 H).

EXAMPLE 6(78)14-oxa-14-(4-fluoro-3-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.50 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.24 (d, J=1.90 Hz, 3 H) 2.25 (m, J=1.92Hz, 1 H) 2.42 (m, 1 H) 2.59 (m, 1 H) 3.27 (m, 1 H) 3.49 (m, 1 H) 3.75(m, 1 H) 4.01 (m, 4 H) 6.66 (m, 2 H) 6.91 (t, J=9.00 Hz, 1 H) 8.08 (s, 1H).

EXAMPLE 6(79)14-oxa-14-(2,3,4-trichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.41 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.36 (m, 2 H) 2.67 (m, 1 H) 3.28 (ddd,J=13.20, 10.40, 5.22 Hz, 1 H) 3.54 (ddd, J=13.20, 10.40, 4.94 Hz, 1 H)3.80 (m, 1 H) 4.06 (m, 3 H) 4.28 (dd, J=9.75, 2.61 Hz, 1 H 6.83 (d,J=9.07 Hz, 1 H 7.34 (d, J=9.07 Hz, 1 H 8.08 s, 1 H).

EXAMPLE 6(80)14-oxa-14-(2-chloro-4-fluorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.33 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.28 (m, 1 H) 2.45 (m, 1 H) 2.66 (m, 1 H)3.31 (ddd, J=13.20, 10.40, 5.22 Hz, 1 H) 3.55 (ddd, J=13.20, 10.40, 4.94Hz, 1 H) 3.80 (m, 1 H) 4.01 (m , 2 H) 4.13 (m, 1 H) 4.23 (dd, J=9.60,1.80 Hz, 1 H) 6.91 (m, 2 H) 7.15 (dd, J=7.97, 3.02 Hz, 1 H) 8.08 (s, 1H).

EXAMPLE 6(81)14-oxa-14-(4-chloro-3-nitrophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.37 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 2.03 (m, 1 H) 2.29 (m, 1 H) 2.45 (m, 1 H) 2.62 (m, 1 H)3.27 (ddd, J=13.50, 10.10, 5.36 Hz, 1 H) 3.47 (ddd, J=13.50, 10.10, 5.49Hz, 1 H) 3.68 (m, 1 H) 3.89 (m, 1 H) 4.10 (m, 2 H) 4.51 (dd, J=9.89,2.75 Hz, 1 H) 7.09 (dd, J=9.00, 2.90 Hz, 1 H) 7.43 (d, J=9.00 Hz, 1 H)7.49 (d, J=2.90 Hz, 1 H) 8.11 (s, 1 H).

EXAMPLE 6(82)14-oxa-14-(2,4-dichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.29 (m, 1 H) 2.45 (m, 1 H) 2.66 (m, 1 H)3.29 (ddd, J=13.32, 10.40, 5.22 Hz, 1 H) 3.55 (ddd, J=13.32, 10.40, 5.22Hz, 1 H) 3.80 (m, 1 H) 4.00 (m , 2 H) 4.14 (m, 1 H) 4.25 (dd, J=9.60,1.80 Hz, 1 H) 6.86 (d, J=8.79 Hz, 1 H) 7.20 (dd, J=8.79, 2.47 Hz, 1 H)7.38 (d, J=2.47 Hz, 1 H) 8.08 (s, 1 H).

EXAMPLE 6(83)14-oxa-14-(4-chloro-3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 2.00 (m, 1 H) 2.27 (m, 1 H) 2.44 (m, 1 H) 2.62 (m, 1 H)3.29 (m, 1 H) 3.48 (m, 1 H) 3.69 (m, 1 H) 4.01 (m, 3 H) 4.33 (dd,J=9.75, 2.88 Hz, 1 H) 7.01 (dd, J=8.80, 2.90 Hz, 1 H) 7.21 (d, J=2.90Hz, 1 H) 7.40 (d, J=8.80 Hz, 1 H) 8.10 (s, 1 H).

EXAMPLE 6(84)14-oxa-14-(2,4-dimethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.16 (s, 3 H) 2.26 (s, 3 H) 2.26 (m, 1 H)2.43 (m, 1 H) 2.61 (m, 1 H) 3.25 (ddd, J=13.30, 10.30, 5.22 Hz, 1 H)3.51 (ddd, J=13.30, 10.30, 5.22 Hz, 1 H) 3.79 (m, 1 H) 3.95 (m, 2 H)4.12 (m, 2 H) 6.68 (d, J=8.24 Hz, 1 H) 6.95 (m, 2 H) 8.07 (s, 1 H).

EXAMPLE 6(85)14-oxa-14-(3-ethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.34 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.23 (t, J=7.69 Hz, 3 H) 1.94 (m, 1 H) 2.24 (m, 1 H) 2.42(m, 1 (m, 3 H) 3.27 (ddd, J=13.30, 10.40, 5.49 Hz, 1 H) 3.51 (ddd,J=13.30, 10.40, 5.22 Hz, 1 H) 3.78 (m, 1 H) 3.94 (m, 2 H) 4.07 (m, 1 H)4.16 (dd, J=9.60, 3.00 Hz, 1 H) 6.70 (m, 2 H) 6.84 (d, J=7.97 Hz, 1 H)7.21 (t, J=7.69 Hz, 1 H) 8.08 (s, 1 H).

EXAMPLE 6(86)14-oxa-14-(3-methyl-4-methylthiophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.36 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.38 (m, J=14.28 Hz, 2 H) 2.36 (s, 3 H)2.40 (s, 3 H) 2.60 (m, 1 H) 3.26 (ddd, J=13.30, 10.40, 5.22 Hz, 1 H)3.50 (ddd, J=13.30, 10.40, 5.36 Hz, 1 H) 3.75 (m, 1 H) 4.04 (m, 4 H)6.72 (m, 2 H) 7.17 (d, J=7.97 Hz, 1 H) 8.08 (s, 1 H).

EXAMPLE 6(87)14-oxa-14-(4-chloro-3,5-dimethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.36 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.34 (m, 2 H) 2.34 (s, 6 H) 2.59 (m, 1 H)3.25 (ddd, J=13.30, 10.50, 5.49 Hz, 1 H) 3.49 (ddd, J=13.30, 10.50, 5.22Hz, 1 H) 3.76 (m, 1 H) 3.91 (m , 2 H) 4.09 (m, 2 H) 6.61 (s, 2 H) 8.08(s, 1 H).

EXAMPLE 6(88)14-oxa-14-(2,3,5-trifluorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.32 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.28 (m, 1 H) 2.44 (m, 1 H) 2.62 (m, 1 H)3.31 (m, 1 H) 3.51 (m, 1 H) 3.72 (m, 1 H) 4.05 (m, 3 H) 4.32 (dd,J=9.75, 2.88 Hz, 1 H) 6.55 (m, 2 H) 8.09 (s, 1 H).

EXAMPLE 6(89)14-oxa-14-(4-fluoro-3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.36 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.98 (m, 1 H) 2.27 (m, 1 H) 2.44 (m, 1 H) 2.60 (m, 1 H)3.29 (ddd, J=13.30, 10.20, 5.08 Hz, 1 H) 3.48 (ddd, J=13.30, 10.20, 4.94Hz, 1 H) 3.70 (m, 1 H) 4.01 (m, 3 H) 4.27 (dd, J=9.61, 3.02 Hz, 1 H)7.08 (m, 3 H) 8.09 (s, 1 H).

EXAMPLE 6(90)14-oxa-14-(4-chloro-3-fluorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

TLC: Rf 0.41 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.96 (m, 1 H) 2.26 (m, 1 H) 2.43 (m, 1 H) 2.59 (m, 1 H)3.27 (ddd, J=13.32, 10.30, 5.22 Hz, 1 H) 3.48 (ddd, J=13.32, 10.30, 5.40Hz, 1 H) 3.71 (m, 1 H) 3.93 (m , 2 H) 4.08 (m, 1 H) 4.21 (dd, J=9.75,3.16 Hz, 1 H) 6.64 (m, 1 H) 6.72 (dd, J=10.44, 2.75 Hz, 1 H) 7.28 (t,J=8.65 Hz, 1 H) 8.09 (s, 1 H).

EXAMPLE 6(91)(13E,15α)-19-phenoxy-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.22 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 1.63 (m, 7 H) 2.35 (m, 3 H) 3.39 (m, 3 H) 3.78 (m, 1 H)3.94 (t, J=6.18 Hz, 2 H) 4.18 (m, 2 H) 5.09 (m, 2 H) 5.56 (dd, J=15.38,8.52 Hz, 2 H) 5.81 (dd, J=15.38, 5.77 Hz, 1 H) 6.89 (m, 3 H) 7.26 (m, 2H) 8.07 (s, 1 H).

EXAMPLE 6(92)(13E,15α)-20-phenoxy-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.22 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 1.47 (m, 6 H) 1.76 (m, 3 H) 2.35 (m, 3 H) 3.38 (m, 3 H)3.79 (m, 1 H) 3.94 (t, J=6.32 Hz, 2 H) 4.16 (m, 2 H) 4.76 (m, 2 H) 5.55(ddd, J=15.31, 8.58, 0.82 Hz, 1 H) 5.8 0 (dd, J=15.38, 5.77 Hz, 1 H)6.91 (m, 3 H) 7.27 (m, 2 H) 8.08 (s, 1 H).

EXAMPLE 7(1) AND (2)

By the same procedure as described in Example 3, using a correspondingderivative instead of the compound prepared in Reference Example 11, thefollowing compounds of the present invention were obtained.

EXAMPLE 7(1)2-(2-(2-(4-(2-hydroxymethylphenyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.11 (ethyl acetate:n-hexane=3:1);

NMR (CDCl₃) δ 8.02 (s, 1H), 7.59-7.55 (m, 1H), 7.44-7.32 (m, 4H),7.30-7.23 (m, 3H), 4.93-4.86 (m, 1H), 4.58 (d, J=5.4 Hz, 2H), 4.38 (q,J=7.2 Hz, 2H), 3.99-3.87 (m, 1H), 3.51-3.30 (m, 2H), 3.16-3.05 (m, 1H),2.68-2.45 (m, 3H), 2.03-1.89 (m, 1H), 1.81 (t, J=5.4 Hz, 1H), 1.38 (t,J=7.2 Hz, 3H).

EXAMPLE 7(2)2-(2-(2-(4-(2-propoxyethyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.13 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.00 (s, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz,2H), 4.79 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.93 (m, 1H), 3.61 (t, J=7.2Hz, 2H), 3.44-3.32 (m, 4H), 3.01 (m, 1H), 2.87 (t, J=7.2 Hz, 2H),2.64-2.34 (m, 3H), 1.88 (m, 1H), 1.68-1.48 (m, 2H), 1.40 (t, J=7.2 Hz,3H), 0.89 (t, J=7.2 Hz, 3H).

EXAMPLES 8(1) AND (2)

By the same procedure as described in Example 2, using the compoundprepared in Example 7(1) or 7(2) instead of the compound prepared inExample 1, the following compounds of the present invention wereobtained.

EXAMPLE 8(1)2-(2-(2-(4-(2-hydroxymethylphenyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.16 (methylene chloride:methanol=5:1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.58-7.53 (m, 1H), 7.45-7.32 (m, 4H),7.29-7.22 (m, 3H), 4.83-4.76 (m, 1H), 4.61 (s, 2H), 4.05-3.96 (m, 1H),3.37-3.21 (m, 3H), 2.70-2.44 (m, 3H), 2.07-1.94 (m, 1H).

EXAMPLE 8(2)2-(2-(2-(4-(2-propoxyethyl)phenyl)-5-oxopyrrolidin-1-yl)ethylthio)thiazole-4-carboxylicacid

TLC: Rf 0.27 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.06 (s, 1H), 7.25 (d, J=8.1 Hz, 2H), 7.13 (d, J=8.1 Hz,2H), 4.67 (m, 1H), 3.94 (m, 1H), 3.67 (t, J=6.9 Hz, 2H), 3.43 (t, J=6.9Hz, 2H), 3.35-3.04 (m, 3H), 2.90 (t, J=6.9 Hz, 2H), 2.70-2.36 (m, 3H),1.94 (m,1H), 1.69-1.50 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

EXAMPLE 9(13E,15α)-5-hydroxy-5-(4-(2-(2-ethyl-2-methylbutanoyloxy)ethoxycarbonyl)thiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprost-13-ene

The compound prepared in Example 2(2) (312 mg),2-(2-ethyl-2-methylbutanoyloxy)ethanol (700 mg) and triethylamine (0.33mL) was dissolved into ethyl acetate (8 mL) and then the mixture wasstirred for 5 minutes. 1-Methanesulfonyloxybenzotriazole (341 mg) wasadded to the reaction solution, which was stirred at room temperaturefor 3 hours. Water was added to the reaction solution, which wasextracted with ethyl acetate. The extract was washed with water, anaqueous saturated sodium hydrogen carbonate solution and brinesequentially, dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=1:3→ethyl acetate) to give the compound of thepresent invention (316 mg) having the following physical data.

TLC: Rf 0.30 (ethyl acetate);

NMR (CDCl₃): δ 8.00 (s, 1H), 5.79 (d, J=15.6, 5.7 Hz, 1H), 5.54 (ddd,J=15.6, 8.4, 1.0 Hz, 1H), 4.55 (m, 2H), 4.40 (m, 2H), 4.20 (m, 1H), 4.10(m, 1H), 3.79 (m, 1H), 3.53-3.31 (m, 3H), 2.50-2.19 (m, 3H), 2.09 (d,J=4.7 Hz, 1H), 1.83-1.61 (m, 3H), 1.58-1.20 (m, 10H), 1.10 (s, 3H),0.95-0.78 (m, 9H).

EXAMPLE 9(1) TO EXAMPLE 9(4)

By the same procedure as described in Example 9, using a correspondingcarboxylic acid derivative instead of the compound prepared in Example2(2), the following compounds of the present invention were obtained.

EXAMPLE 9(1)(13E,15α)-15-hydroxy-1,6-(1,4-interphenylene)-9-oxo-2,3,4,5-tetranor-8-azaprost-13-enoicacid 2-(2-ethyl-2-methylbutanoyloxy)ethyl ester

TLC: Rf 0.28 (ethyl acetate);

NMR (CDCl₃): δ 7.92 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 5.59 (dd,J=15.6, 6.3 Hz, 1H), 5.39 (dd, J=15.6, 8.7 Hz, 1H), 4.55 (m, 2H), 4.41(m, 2H), 4.12 (m, 1H), 3.80 (m, 2H), 3.11 (m, 1H), 3.00-2.80 (m, 2H),2.44-2.25 (m, 2H), 2.16 (m, 1H), 1.79-1.23 (m, 14H), 1.10 (s, 3H),0.95-0.78 (m, 9H).

EXAMPLE 9(2)(13E,15α)-15-hydroxy-1,5-(2,5-interthienylene)-9-oxo-2,3,4-trinor-8-azaprost-13-enoicacid 2-(2-ethyl-2-methylbutanoyloxy)ethyl ester

TLC: Rf 0.26 (ethyl acetate);

NMR (CDCl₃): δ 7.62 (d, J=3.3 Hz, 1H), 6.81 (d, J=3.3 Hz, 1H), 5.68 (dd,J=15.6, 6.3 Hz, 1H), 5.48 (dd, J=15.6, 8.7 Hz, 1H), 4.47 (m, 2H), 4.38(m, 2H), 4.18-4.00 (m, 2H), 3.60 (m, 1H), 2.99 (m, 1H), 2.83 (t, J=7.8Hz, 2H), 2.50-2.16 (m, 3H), 1.97-1.23 (m, 16H), 1.10 (s, 3H), 0.98-0.80(m, 9H).

EXAMPLE 9(3) (13E,15α)-15-hydroxy-9-oxo-5-thia-8-azaprost-13-enoic acid2-(2-ethyl-2-methylbutanoyloxy)ethyl ester

TLC: Rf 0.26 (ethyl acetate);

NMR (CDCl₃): δ 5.73 (dd, J=15.3, 5.7 Hz, 1H), 5.52 (dd, J=15.3, 9.0 Hz,1H), 4.28 (s, 4H), 4.15 (m, 2H), 3.66 (m, 1H), 3.09 (m, 1H), 2.77-2.50(m, 4H), 2.49-2.20 (m, 5H), 1.96-1.82 (m, 2H), 1.80-1.22 (m, 14H), 1.10(s, 3H), 0.94-0.80 (m, 9H).

EXAMPLE 9(4)(15α)-5-hydroxy-5-(4-(2-(2-ethyl-2-methylbutanoyloxy)ethoxycarbonyl)thiazol-2-yl)-9-oxo-1,2,3,4-tetranor-5-thia-8-azaprostane

TLC: Rf 0.45 (ethyl acetate);

NMR (CDCl₃): δ 0.85 (m, 9 H) 1.10 (s, 3 H) 1.51 (m, 16 H) 1.98 (m, 1H)2.13 (m, 1 H) 2.39 (m, 3 H) 3.59 (m, 6 H) 4.39 (m, 2 H) 4.52 (m, 2 H)7.97 (s, 1 H).

EXAMPLE 1014-oxa-14-(3,5-dichlorophenyl)-5-(4-hydroxymethylthiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane

To a solution of the compound prepared in Example 5(32) (125 mg) intetrahydrofuran (3 mL) was added sodium borohydride (40 mg) and themixture was stirred at room temperature for 1 day. The reaction mixturewas poured into water and extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=1:4) to give thecompound of the present invention (68.9 mg) having the followingphysical data.

TLC: Rf 0.34 (ethyl acetate);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.22 (m, 1 H) 2.38 (m, 1 H) 2.53 (m, 2 H)3.34 (m, 1 H) 3.51 (m, 2 H) 3.93 (m, 2 H) 4.11 (m, 2 H) 4.68 (br. s., 2H) 6.77 (d, J=1.70 Hz, 2 H) 6.99 (t, J=1.70 Hz, 1 H) 7.05 (s, 1 H).

EXAMPLE 11(2R)-2-(3,5-dichlorophenoxymethyl)-1-(2-(4-methoxymethyl-1,3-thiazol-2-ylthio)ethyl)pyrrolidin-5-one

Under an atmosphere of argon, to a solution of the compound prepared inExample 10 (112 mg) in tetrahydrofuran (1 mL) was added sodium hydride(13 mg) and the mixture was stirred at room temperature for 30 minutes.Methyl iodide (0.1 mL) was added to the reaction solution, which wasstirred for 1 hour. Water was added to the reaction mixture, which wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated. Theobtained residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=1:4ethyl acetate) to give the compound of thepresent invention (98.2 mg) having the following physical data.

TLC: Rf 0.44 (ethyl acetate);

NMR (CDCl₃): δ 1.96 (m, 1 H) 2.22 (m, 1 H) 2.38 (ddd, J=16.90, 9.80,5.13 Hz, 1 H) 2.54 (ddd, J=16.90, 9.80, 7.30 Hz, 1 H) 3.42 (s, 3 H) 3.42(m, 3 H) 3.87 (ddd, J=13.55, 7.78, 6.04 Hz, 1 H) 3.97 (dd, J=9.60, 4.00Hz, 1 H) 4.10 (ddd, J=11.63, 7.78, 3.30 Hz, 1 H) 4.18 (dd, J=9.60, 3.90Hz, 1 H) 4.48 (m, 2 H) 6.78 (d, J=1.65 Hz, 2 H) 6.98 (t, J=1.65 Hz, 1 H)7.09 (s, 1 H).

EXAMPLE 122-(2-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxamide

To a solution of the compound prepared in Example 6(32) (300 mg) intoluene (4.0 mL) were added oxalyl chloride (0.07 mL) anddimethylformamide (one drop) and the mixture was stirred at roomtemperature and 40 minutes. The reaction mixture was concentrated anddissolved into anhydrous tetrahydrofuran (2.0 mL). To ammonia water (1.0mL) was added the above tetrahydrofuran solution at 0° C. and themixture was stirred for 30 minutes. The reaction mixture wasconcentrated and extracted with dichloromethane. The organic layer wasdried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was purified by column chromatography on silica gel (ethylacetate) to give the compound of the present invention (280 mg) havingthe following physical data.

TLC: Rf 0.55 (ethyl acetate);

NMR (CDCl₃): δ 8.02 (s, 1H), 7.99 (s, 1H), 7.01 (t, J=1.5 Hz, 1H), 6.78(d, J=1.5 Hz, 2H), 5.65 (s, 1H), 4.17-3.91 (m, 4H), 3.63 (m, 1H), 3.50(m, 1H), 3.31 (m, 1H), 2.53 (m, 1H), 2.40 (m, 1H), 2.22 (m, 1H), 1.92(m, 1H).

EXAMPLES 12(1) TO 12(4)

By the same procedure as described in Example 12, using a correspondingamine derivative, amide derivative or sulfonamide derivative instead ofammonia water, the following compounds of the present invention wereobtained.

EXAMPLE 12(1)2-(2-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-N,N-dimethyl-1,3-thiazole-4-carboxamide

TLC: Rf 0.23 (ethyl acetate);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.23 (m, 1 H) 2.38 (ddd, J=16.93, 9.80,5.00 Hz, 1 H) 2.53 (ddd, J=16.93, 9.70, 7.23 Hz, 1 H) 3.10 (s, 3 H) 3.22(s, 3 H) 3.47 (m, 3 H) 3.92 (m, 2 H) 4.06 (m, 1 H) 4.14 (dd, J=9.60,3.90 Hz, 1 H) 6.77 (d, J=1.74 Hz, 2 H) 6.99 (t, J=1.74 Hz, 1 H) 7.68 (s,1 H).

EXAMPLE 12(2)(2R)-2-(3,5-dichlorophenoxymethyl)-1-(2-(4-(4-methylpiperazin-1-ylcarbonyl)-1,3-thiazol-2-ylthio)ethyl)pyrrolidin-5-one

TLC: Rf 0.55 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.23 (m, 1 H) 2.31 (s, 3 H) 2.46 (m, 6 H)3.47 (m, 3 H) 3.80 (m, 4 H) 3.95 (m, 2 H) 4.08 (m, 2 H) 6.76 (d, J=1.74Hz, 2 H) 6.99 (t, J=1.74 Hz, 1 H ) 7.71 (s, 1 H).

EXAMPLE 12(3)2-(2-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-N-methylsulfonyl-1,3-thiazole-4-carboxamide

TLC: Rf 0.47 (methylene chloride:methanol=9:1);

NMR (DMSO-D6): δ 8.00 (s, 1H), 7.15 (d, J=1.8 Hz, 2H), 7.11 (t, J=1.8Hz, 1H), 4.59 (m, 1H), 4.16-4.00 (m, 2H), 3.70 (m, 1H), 3.50-3.20 (m,2H), 2.97 (s, 3H), 2.60-2.25 (m, 2H), 2.25-2.00 (m, 2H), 1.85 (m, 1H).

EXAMPLE 12(4)N-benzoyl-2-(2-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxamide

TLC: Rf 0.20 (hexane:ethyl acetate=1:2);

NMR (CDC₃): δ 8.21 (s, 1H), 8.00-7.92 (m, 2H), 7.61 (m, 1H), 7.55-7.46(m, 2H), 6.99 (t, J=1.5 Hz, 1H), 6.71 (d, J=1.5 Hz, 2H), 4.10-3.88 (m,4H), 3.72-3.54 (m, 2H), 3.42 (m, 1H), 2.44 (m, 1H), 2.35-2.06 (m, 2H),1.86 (m, 1H).

EXAMPLE 13(1) TO 13(8)

By the same procedure as described in Example 1, using the compoundprepared in Reference Example 3 or a corresponding aldehyde derivative,and the compound prepared in Reference Example 9 or a correspondingamine derivative, the following compounds of the present invention wereobtained.

EXAMPLE 13(1)2-(2-((2R)-2-(2-naphthyloxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.22 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 0.96 (t, J=7.30 Hz, 3 H) 1.44 (m, 2 H) 1.74 (m, 2 H) 2.10(m, 1 H) 2.26 (m, 1 H) 2.41 (m, 1 H) 2.63 (m, 1 H) 3.39 (m, 1 H) 3.51(m, 1 H) 3.64 (m, 1 H) 3.94 (m, 1 H) 4.13 (dd, J=9.60, 3.60 Hz, 1 H)4.21 (m, 1 H) 4.33 (m, 2 H) 4.57 (dd, J=9.60, 3.00 Hz, 1 H) 7.10 (m, 1H) 7.19 (m, 1 H) 7.33 (m, 1 H) 7.42 (m, 1 H) 7.71 (m, 3 H) 7.94 (s, 1H).

EXAMPLE 13(2)2-(2-((2R)-2-(3-ethylphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.28 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 0.97 (t, J=7.30 Hz, 3 H) 1.20 (t, J=7.70 Hz, 3 H) 1.45(m, 2 H) 1.73 (m, 2 H) 2.03 (m, 1 H) 2.21 (m, 1 H) 2.37 (m, 1H) 2.59 (m,3 H) 3.48 (m, 3 H) 3.95 (m, 2 H) 4.14 (m, 1 H) 4.35 (m, 3 H) 6.73 (m, 3H) 7.15 (m, 1 H) 7.98 (s, 1 H).

EXAMPLE 13(3)2-(2-((2R)-5-oxo-2-(3-trifluoromethylphenoxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.63 (ethyl acetate);

NMR (CDCl₃): δ 0.97 (t, J=7.32 Hz, 3 H) 1.45 (m, 2 H) 1.74 (m, 2 H) 2.10(m, 1 H) 2.25 (m, 1 H) 2.40 (ddd, J=16.84, 9.98, 5.22 Hz, 1 H) 2.61(ddd, J=16.84, 9.98, 7.14 Hz, 1 H) 3.32 (ddd, J=13.46, 9.25, 5.68 Hz, 1H) 3.48 (ddd, J=13.46, 9.25, 5.18 Hz, 1 H) 3.62 (ddd, J=13.90, 9.00,5.50 Hz, 1H) 3.88 (ddd, J=13.90, 9.00, 5.50 Hz, 1 H) 4.06 (dd, J=10.34,3.02 Hz, 1H) 4 .17 (m, 1H) 4.32 (t, J=6.68 Hz, 2 H) 4.68 (dd, J=10.34,3.02 Hz, 1 H) 7.09 (m, 1 H) 7.20 (m, 2 H) 7.35 (m, 1 H) 7.96 (s, 1 H).

EXAMPLE 13(4)2-(2-((2R)-5-oxo-2-(3-trifluoromethoxyphenoxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.64 (ethyl acetate);

NMR (CDCl₃): δ 0.97 (t, J=7.32 Hz, 3 H) 1.45 (m, 2 H) 1.74 (m, 2 H) 2.07(m, 1 H) 2.24 (m, 1 H) 2.39 (ddd, J=16.90, 10.00, 5.20 Hz, 1 H) 2.59(ddd, J=16.90, 10.20, 7.15 Hz, 1 H) 3.33 (ddd, J=13.40, 9.00, 5.80 Hz, 1H) 3.49 (ddd, J=13.40, 9.20, 5.20 Hz, 1 H) 3.60 (ddd, J=13.70, 9.00,5.20 Hz, 1 H) 3.89 (ddd, J=13.70, 9.20, 5.80 Hz, 1 H) 4.02 (dd, J=10.25,3.48 Hz, 1 H) 4.15 (m, 1 H) 4.32 (t, J=6.68 Hz, 2 H) 4.57 (dd, J=10.25,3.11 Hz, 1 H) 6.82 (m, 3 H) 7.24 (m, 1 H) 7.97 (s, 1 H).

EXAMPLE 13(5)(3-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-ylmethyl)phenoxy)aceticacid ethyl ester

TLC: Rf 0.25 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): 1.30 (t, J=7.14 Hz, 3 H) 1.96 (m, 1 H) 2.21 (m, 1 H) 2.46(m, 1 H) 2.63 (m, 1 H) 3.87 (m, 3 H) 4.21 (d, J=15.11 Hz, 1 H) 4.27 (q,J=7.14 Hz, 2 H) 4.56 (s, 2 H) 4.83 (d, J=15.11 Hz, 1 H) 6.68 (d, J=1.65Hz, 2 H) 6.76 (m, 1 H) 6.81 (m, 1 H) 6.88 (m, 1 H) 6.97 (t, J=1.65 Hz, 1H) 7.20 (t, J=7.80 Hz, 1 H).

EXAMPLE 13(6)(2E)-3-(3-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-ylmethyl)phenyl)-2-propenoicacid methyl ester

TLC: Rf 0.25 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.23 (m, 1 H) 2.48 (m, 1 H) 2.66 (m, 1 H)3.81 (s, 3 H) 3.88 (m, 3 H) 4.40 (d, J=15.11 Hz, 1 H) 4.74 (d, J=15.11Hz, 1 H) 6.38 (d, J=16.21 Hz, 1 H ) 6.62 (d, J=1.79 Hz, 2 H) 6.95 (t,J=1.79 Hz, 1H) 7.30 (m, 2 H) 7.38 (m, 2 H) 7.59 (d, J=16.21 Hz, 1H).

EXAMPLE 13(7)3-(3-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-ylmethyl)phenyl)propanoicacid methyl ester

TLC: Rf 0.22 (hexane:ethyl acetate=1:1);

NMR (CDCl₃) δ 1.96 (m, 1 H) 2.21 (m, 1 H) 2.56 (m, 4 H) 2.88 (t, J=7.69Hz, 2 H) 3.66 (s, 3 H) 3.86 (m, 3 H) 4.25 (d, J=15.11 Hz, 1 H) 4.80 (d,J=15.11 Hz, 1 H) 6.66 (d, J=1.65 Hz, 2 H) 6.97 (t, J=1.65 Hz, 1 H) 7.08(m, 3 H) 7.20 (t, J=7.83 Hz, 1 H).

EXAMPLE 13(8)2-(2-((2R)-5-oxo-2-(pyridin-2-yloxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid ethyl ester

TLC: Rf 0.50 (ethyl acetate);

NMR (CDCl₃): δ 1.38 (t, J=7.00 Hz, 3 H) 1.98 (m, 1 H) 2.21 (m, 1 H) 2.34(m, 1 H) 2.52 (m, 1 H) 3.50 (m, 3 H) 3.97 (m, 1 H) 4.16 (m, 1 H) 4.38(m, 3 H) 4.53 (dd, J=12.00, 4.0 0 Hz, 1 H) 6.69 (m, 1 H) 6.88 (m, 1 H)7.56 (m, 1 H) 8.01 (s, 1 H) 8.10 (m, 1 H).

EXAMPLE 14(1) TO 14(52)

By the same procedure as described in Example 2, using the compoundprepared in Example 13(1) to 13(8) or a corresponding ester instead ofthe compound prepared in Example 1, the following compounds of thepresent invention were obtained.

EXAMPLE 14(1)(15α,13E)-15-hydroxy-9-oxo-17-phenyl-18,19,20-trinor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 7.37-7.15 (m, 5H), 5.78 (dd, J=15.3, 5.4 Hz, 1H), 5.60(ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.25-4.10 (m, 2H), 3.64 (m, 1H), 3.12(m, 1H), 2.82-2.10 (m, 12H), 2.00-1.70 (m, 5H).

EXAMPLE 14(2)(15α,13E)-15-hydroxy-9-oxo-18-phenyl-19,20-dinor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (CDCl₃) δ 7.37-7.15 (m, 5H), 5.72 (dd, J=15.3, 5.7 Hz, 1H), 5.50(dd, J=15.3, 8.4 Hz, 1H), 4.65-4.08 (m, 4H), 3.63 (m, 1H), 3.10 (m, 1H),2.72-2.19 (m, 11H), 1.99-1.50 (m, 7H).

EXAMPLE 14(3)2-(2-((2R)-5-oxo-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.59 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.07 (m, 3 H) 2.31 (m, 1 H) 2.47 (m, 1 H) 2.64 (m, 3 H)2.83 (m, 2 H) 3.28 (m, 1 H) 3.51 (m, 1 H) 3.73 (m, 1 H) 4.04 (m, 3 H)4.26 (dd, J=10.00, 3.00 Hz, 1 H) 7.02 (m, 1 H) 7.27 (m, 1 H) 7.70 (m, 1H) 8.09 (s, 1 H).

EXAMPLE 14(4)2-(2-((2R)-2-(3,5-difluorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.52 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.23 (m, 1 H) 2.41 (ddd, J=17.10, 9.90,5.50 Hz, 1 H) 2.58 (ddd, J=17.10, 10.10, 7.10 Hz, 1 H) 3.26 (ddd,J=13.50, 10.00, 5.40 Hz, 1 H) 3.48 (dd d, J=13.50, 10.00, 5.40 Hz, 1 H)3.65 (ddd, J=13.50, 10.00, 5.40 Hz, 1 H) 3.90 (m, 1 H) 3.95 (dd, J=9.90,4.70 Hz, 1 H) 4.08 (m, 1 H) 4.23 (dd, J=9.90, 3.00 Hz, 1 H) 6.43 (m, 3H) 8.08 (s, 1 H).

EXAMPLE 14(5)2-(2-((2R)-2-(4-methoxy-2-nitrophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 1.91 (m, 1 H) 2.28 (m, 1 H) 2.43 (ddd, J=17.00, 10.20,6.60 Hz, 1 H) 2.60 (ddd, J=17.00, 10.20, 6.60 Hz, 1 H) 3.34 (ddd,J=13.20, 10.20, 5.20 Hz, 1 H) 3.51 (d dd, J=13.20, 10.20, 5.20 Hz, 1 H)3.76 (m, 1 H) 3.82 (s, 3 H) 4.09 (m, 3 H) 4.25 (m, 1 H) 7.04 (d, J=9.00Hz, 1 H) 7.11 (dd, J=9.00, 3.00 Hz, 1 H) 7.41 (d, J=3.00 Hz, 1 H) 8.07(s, 1 H).

EXAMPLE 14(6)2-(2-((2R)-2-(4-acetyl-3-fluorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.50 (chloroform:methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 1.99 (m, 1 H) 2.28 (m, 1 H) 2.44 (m, 1 H) 2.59 (d, J=4.90Hz, 3 H) 2.59 (m, 1 H) 3.28 (ddd, J=13.50, 10.40, 5.40 Hz, 1 H) 3.48(ddd, J=13.50, 10.40, 5.40 Hz, 1 H) 3.70 (m, 1 H) 3.94 (ddd, J=13.50,10.40, 5.40 Hz, 1H) 4.10 (m, 2 H) 4.33 (dd, J=9.60, 3.00 Hz, 1 H) 6.65(dd, J=12.50, 2.50 Hz, 1 H) 6.76 (dd, J=8.65, 2.50 Hz, 1 H) 7.89 (t,J=8.65 Hz, 1 H) 8.10 (s, 1 H).

EXAMPLE 14(7)2-(2-((2R)-2-(3-ethynylphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.48 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.25 (m, 1 H) 2.42 (m, 1 H) 2.59 (m, 1 H)3.08 (s, 1 H) 3.27 (ddd, J=13.50, 10.20, 5.00 Hz, 1 H) 3.49 (ddd,J=13.50, 10.20, 5.00 Hz, 1 H) 3.74 (m, 1 H) 4.18 (dd, J=10.00, 3.00 Hz,1 H) 6.88 (m, 1 H) 7.00 (m, 1 H) 7.13 (m, 1 H) 7.24 (m, 1 H) 8.08 (s, 1H).

EXAMPLE 14(8)2-(2-((2R)-2-(4-formyl-3-methoxyphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.48 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 2.02 (m, 1 H) 2.29 (m, 1 H) 2.45 (ddd, J=17.00, 10.00,7.00 Hz, 1 H) 2.63 (ddd, J=17.00, 10.00, 7.00 Hz, 1 H) 3.29 (ddd,J=13.40, 10.20, 5.20 Hz, 1 H) 3.49 (d dd, J=13.40, 10.20, 5.20 Hz, 1 H)3.71 (m, 1 H) 3.90 (s, 3 H) 3.94 (m, 1 H) 4.11 (m, 2 H) 4.38 (m, 1 H)6.44 (d, J=2.20 Hz, 1 H) 6.56 (m, 1 H) 7.81 (d, J=8.50 Hz, 1 H) 8.10 (s,1 H) 10.29 (s, 1 H).

EXAMPLE 14(9)2-(2-((2R)-2-(2-chloro-3,5-difluorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.54 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.96 (m, 1 H) 2.38 (m, 2 H) 2.69 (m, 1 H) 3.29 (m, 1 H)3.55 (m, 1 H) 3.78 (m, 1 H) 4.00 (m, 2 H) 4.17 (m, 1 H) 4.33 (dd,J=10.20, 2.80 Hz, 1 H) 6.58 (m, 2 H) 8.09 (s, 1 H).

EXAMPLE 14(10)(15α,13E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-18-phenoxy-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.59 (chloroform:methanol=4:1);

NMR (CDCl₃): δ 8.07 (s, 1H), 7.31-7.25 (m, 2H), 6.97-6.87 (m, 3H), 5.82(dd, J=15.0, 5.1 Hz, 1H), 5.59 (dd, J=15.0, 8.4 Hz, 1H), 4.30-4.24 (m,1H), 4.18-4.12 (m, 1H), 4.00 (t, J=5.7 Hz, 2H), 3.86-3.74 (m, 1H),3.56-3.27 (m, 5H), 2.53-2.18 (m, 3H), 2.10-1.76 (m, 5H).

EXAMPLE 14(11)(15α,13E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-17-phenoxy-1,2,3,4,18,19,20-heptanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.38 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.31-7.26 (m, 2H), 6.98-6.88(m, 3H), 5.86(dd, J=15.3, 5.7 Hz, 1H), 5.64 (dd, J=15.3, 8.4 Hz, 1H), 4.53-4.48 (m,1H), 4.19-4.07 (m, 3H), 3.81-3.74 (m, 1H), 3.50-3.30 (m, 3H), 2.4 6-2.19(m, 3H), 2.04-1.99 (m, 1H), 1.79-1.73 (m, 1H), 1.30-1.24 (m, 1H),0.93-0.83 (m, 1H).

EXAMPLE 14(12)2-(2-((2R)-2-(3,5-dichlorophenylthiomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.56 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.32 (m, 2 H) 2.54 (ddd, J=18.30, 10.50,6.00 Hz, 1 H) 3.17 (dd, J=12.90, 6.90 Hz, 1 H) 3.40 (m, 4 H) 3.96 (m, 2H) 7.18 (t, J=1.80 Hz, 1 H) 7.21 (d, J=1.80 Hz, 2 H) 8.11 (s, 1 H).

EXAMPLE 14(13)(15α,13E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-18-(naphthalen-2-yl)-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.26 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.03 (s, 1H), 7.81-7.74 (m, 4H), 7.58 (s, 1H), 7.47-7.39(m, 2H), 7.31-7.28 (m, 1H), 5.76 (dd, J=15.3, 5.4 Hz, 1H), 5.52 (dd,J=15.3, 8.1 Hz, 1H), 4.22-4.07 (m, 4H), 3.79-3.72 (m, 1H), 3.45-3.25 (m,3H), 2.79 (t, J=7.2 Hz, 2H), 2.44-2.18 (m, 3H), 1.84-1.55 (m, 5H).

EXAMPLE 14(14)(15α,13E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-19-(naphthalen-2-yl)-1,2,3,4,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.22 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.07 (s, 1H), 7.81-7.74 (m, 3H), 7.59 (s, 1H), 7.47-7.39(m, 2H), 7.33-7.28 (m, 1H), 5.74 (dd, J=15.3, 6.0 Hz, 1H), 5.49 (dd,J=15.9, 9.0 Hz, 1H), 4.16-4.07 (m, 4H), 3.79-3.72 (m, 1H), 3.45-3.25 (m,5H), 2.79-2.74 (m, 2H), 2.44-2.18 (m, 3H), 1.84-1.55 (m, 5H).

EXAMPLE 14(15)(15α,13E,18E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-19-naphthalen-2-yl-1,2,3,4,19,20-hexanor-5-thia-8-azaprost-13,18-diene

TLC: Rf 0.22 (chloroform:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 8.06 (s, 1H), 7.78-7.74 (m, 3H), 7.65 (s, 1H), 7.55 (dd,J=8.7, 2.8 Hz, 1H), 7.46-7.39 (m, 2H), 6.55 (d, J=15.3 Hz, 1H),6.36-6.27 (m, 1H), 5.84 (dd, J=15.3, 5.4 Hz, 1H), 5.59 (dd, J=15.0, 9.6Hz, 1H), 4.30-4.12 (m, 2H), 3.86-3.71 (m, 4H), 3.47-3.32 (m, 3H),2.47-2.18 (m, 4H), 1.79-1.69 (m, 3H).

EXAMPLE 14(16)2-(2-((2R)-2-benzyloxymethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.36 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 8.06 (s, 1 H), 7.40-7.24 (m, 5 H), 4.53 (s, 2 H),3.85-3.82 (m, 2 H), 3.75-3.56 (m, 2H), 3.52-3.34 (m, 2H), 3.24 (m, 1H),2.57-2.25 (m, 2H), 2.12 (m, 1H), 1.78 (m, 1H).

EXAMPLE 14(17)2-(2-((2R)-2-(3-dimethylaminophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.44 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.24 (m, 1 H) 2.42 (ddd, J=17.00, 10.20,5.70 Hz, 1 H) 2.60 (ddd, J=17.00, 10.20, 6.60 Hz, 1 H) 2.94 (s, 6 H)3.28 (ddd, J=13.20, 10.40, 5.20 Hz, 1 H) 3.52 (ddd, J=13.20, 10.40, 5.20Hz, 1 H) 3.92 (m, 4 H) 4.18 (dd, J=9.90, 3.00 Hz, 1 H) 4.79 (br. s., 1H) 6.26 (m, 2 H) 6.41 (m, 1 H) 7.14 (t, J=8.40 Hz, 1 H).

EXAMPLE 14(18)3-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-ylmethyl)phenoxyaceticacid

TLC: Rf 0.31 (chloroform:methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.23 (m, 1 H) 2.52 (m, 1 H) 2.68 (m, 1 H)3.88 (m, 3 H) 4.26 (d, J=15.11 Hz, 1 H) 4.59 (s, 2 H) 4.78 (d, J=15.11Hz, 1 H) 6.67 (d, J=1.65 Hz, 2 H) 6.82 (m, 3 H) 6.96 (t, J=1.65 Hz, 1 H)7.19 (t, J=7.83 Hz, 1 H).

EXAMPLE 14(19)(2E)-3-(3-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-ylmethyl)phenyl)-2-propenoicacid

TLC: Rf 0.46 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.98 (m, 1 H) 2.25 (m, 1 H) 2.52 (m, 1 H) 2.69 (m, 1 H)3.86 (m, 3 H) 4.41 (d, J=15.38 Hz, 1 H) 4.76 (d, J=15.38 Hz, 1 H) 6.42(d, J=16.21 Hz, 1 H) 6.63 (d, J=1.79 Hz, 2 H) 6.96 (t, J=1.79 Hz, 1 H)7.31 (m, 2 H) 7.42 (m, 2 H) 7.69 (d, J=16.21 Hz, 1 H).

EXAMPLE 14(20)3-(3-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-ylmethyl)phenyl)propanoicacid

TLC: Rf 0.64 (ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.22 (m, 1 H) 2.48 (m, 1 H) 2.65 (m, 3 H)2.89 (t, J=7.51 Hz, 2 H) 3.87 (m, 3 H) 4.26 (d, J=15.01 Hz, 1 H) 4.79(d, J=15.01 Hz, 1 H) 6.66 (d, J=1.83 Hz, 2 H) 6.97 (t, J=1.83 Hz, 1 H)7.09 (m, 3 H) 7.20 (m, 1 H).

EXAMPLE 14(21)5-(3-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylicacid

TLC: Rf 0.23 (methylene chloride:methanol=15:1);

NMR (CDCl₃): δ 7.69 (d, J=3.6 Hz, 1H), 7.00 (t, J=1.8 Hz, 1H), 6.82 (d,J=3.6 Hz, 1H), 6.75 (d, J=1.8 Hz, 2H), 4.06-3.86 (m, 2H), 3.69 (m, 1H),3.17 (m, 1H), 2.88 (t, J=7.5 Hz, 2H), 2.54 (m, 1H), 2.41 (m, 1H), 2.21(m, 1H), 2.10-1.78 (m, 4H).

EXAMPLE 14(22)4-(2-((2R)-2-(3,5-dichlorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethyl)benzoicacid

TLC: Rf 0.34 (methylene chloride:methanol=15:1);

NMR (CDCl₃): δ 8.02 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.00 (t,J=2.1 Hz, 1H), 6.74 (d, J=2.1 Hz, 2H), 3.98-3.72 (m, 4H), 3.37 (m, 1H),3.02 (m, 1H), 2.92 (m, 1H), 2.52 (m, 1H), 2.39 (m, 1H), 2.16 (m, 1H),1.86 (m, 1H).

EXAMPLE 14(23)2-(2-((2R)-5-oxo-2-(pyridin-2-yloxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.24 (methylene chloride:methanol:acetic acid=90:10:0.3);

NMR (CDCl₃): δ 2.03 (m, 1 H) 2.24 (m, 1 H) 2.41 (m, 1 H) 2.58 (m, 1 H)3.28 (m, 1 H) 3.41 (m, 1 H) 3.75 (m, 2 H) 4.05 (m, 1 H) 4.28 (dd,J=11.50, 4.40 Hz, 1 H) 4.75 (m, 1 H) 6.75 (d, J=8.20 Hz, 1 H) 6.92 (m, 1H) 7.61 (m,1 H) 8.08 (s, 1 H) 8.10 (m, 1 H).

EXAMPLE 14(24)2-(2-((2R)-5-oxo-2-(quinolin-5-yloxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.16 (chloroform:methanol=9:1);

NMR (DMSO-D6): δ 8.68 (dd, J=4.2, 1.2 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H),7.79 (s, 1H), 7.69-7.53 (m, 2H), 7.50 (dd, J=8.4, 4.2 Hz, 1H), 7.17 (d,J=6.9 Hz, 1H), 4.51 (m, 1H), 4.30-4.12 (m, 2H), 3.80 (m, 1H), 3.50-3.10(m, 3H), 2.55-2.38 (m, 1H), 2.35-2.05 (m, 2H), 1.98 (m, 1H).

EXAMPLE 14(25)2-(2-((2R)-5-oxo-2-(quinolin-6-yloxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.16 (chloroform:methanol=9:1);

NMR (DMSO-D6): δ 8.71 (dd, J=4.5, 1.5 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H),7.88 (d, J=9.0 Hz, 1H), 7.79 (s, 1H), 7.55 (m, 1H), 7.43 (dd, J=8.4, 4.5Hz, 1H), 7.37 (dd, J=9.0, 3.0 Hz, 1H), 4.54 (brs, 1H), 4.18-4.06 (m,2H), 3.75 (m, 1H), 3.50-3.10 (m, 3H), 2.60-2.30 (m, 1H), 2.30-2.02 (m,2H), 1.93 (m, 1H).

EXAMPLE 14(26)2-(2-((2R)-5-oxo-2-(quinolin-8-yloxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.08 (chloroform:methanol=9:1);

NMR (DMSO-D6): δ 8.84 (dd, J=4.5, 2.1 Hz, 1H), 8.31 (s, 1H), 8.27 (d,J=6.9 Hz, 1H), 7.56-7.44 (m, 3H), 7.23 (dd, J=6.6, 2.1 Hz, 1H), 4.49 (d,J=8.1 Hz, 1H), 4.27-4.13 (m, 2H), 3.86 (m, 1H), 3.65-3.20 (m, 3H), 2.62(m, 1H), 2.30-2.05 (m, 2H), 1.95 (m, 1H).

EXAMPLE 14(27)2-(2-((2R)-5-oxo-2-(2-phenylethoxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.23 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.33-7.24 (m, 2H), 7.23-7.14 (m, 3H),3.86-3.51 (m, 4H), 3.69 (t, J=6.6 Hz, 2H), 3.44 (dd, J=9.9, 5.7 Hz, 1H),3.29 (m, 1H), 3.16 (m, 1H), 2.86 (t, J=6.6 Hz, 2H), 2.52-2.24 (m, 2H),2.11 (m, 1H), 1.71 (m, 1H).

EXAMPLE 14(28)2-(2-((2R)-5-oxo-2-(2-phenylpropoxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.23 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.08 (s, 1H), 7.33-7.24 (m, 2H), 7.23-7.13 (m, 3H),3.91-3.79 (m, 2H), 3.72 (m, 1H), 3.59-3.38 (m, 5H), 3.31 (m, 1H),2.70-2.61 (m, 2H), 2.56-2.28 (m, 2H), 2.13 (m, 1H), 1.96-1.70 (m, 3H).

EXAMPLE 14(29)(15α,13E)-15-hydroxy-9-oxo-3,7-(1,3-interphenylene)-3-thia-20-ethyl-4,5,6-trinor-8-azaprost-13-enoicacid

TLC: Rf 0.28 (chloroform:methanol=6:1);

NMR (CDCl₃): δ 0.88 (m, 3 H) 1.26 (m, 10 H) 1.53 (m, 2 H) 1.76 (m, 1 H)2.20 (m, 1 H) 2.44 (m, 2 H) 3.59 (s, 2 H) 3.90 (m, 1H) 3.97 (d, J=14.65Hz, 1 H) 4.14 (m, 1 H) 4.78 (d, J=14.65 Hz, 1 H) 5.43 (ddd, J=15.60,8.56, 1.19 Hz, 1 H) 5.65 (dd, J=15.60, 5.40 Hz, 1 H) 7.07 (d, J=8.06 Hz,1 H) 7.23 (m, 2 H) 7.32 (m, 1 H).

EXAMPLE 14(30)2-(2-((2R)-5-oxo-2-(pyridin-4-yloxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.32 (methylene chloride:methanol:water=80:20:1);

NMR (DMSO-D6): δ 1.86 (m, 1 H) 2.30 (m, 3 H) 3.36 (m, 3 H) 3.77 (m, 1 H)4.11 (m, 2 H) 4.37 (m, 1 H) 6.96 (d, J=6.00 Hz, 2 H) 8.36 (m, 3 H) 13.09(br. s., 1 H).

EXAMPLE 14(31)(15α,13E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-17-phenyl-1,2,3,4,18,19,20-heptanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.47 (methylene chloride:methanol=5:1);

NMR (CDCl₃): δ 1.83 (m, 3 H) 2.34 (m, 4 H) 2.67 (m, 2 H) 3.33 (m, 2 H)3.46 (m, 1 H) 3.83 (m, 1 H) 4.15 (m, 2 H) 5.58 (ddd, J=15.33, 8.65, 1.28Hz, 1 H) 5.81 (dd, J=15.30, 5.40 Hz, 1 H) 7.25 (m, 5 H) 8.07 (s, 1 H).

EXAMPLE 14(32)2-(2-((2R)-5-oxo-2-(2-trifluoromethoxyphenoxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.38 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.28 (m, 1 H) 2.44 (m, 1 H) 2.61 (m, 1 H)3.32 (m, 1 H) 3.50 (m, 1 H) 3.75 (m, 1 H) 4.01 (m, 2 H) 4.14 (m, 1 H)4.25 (dd, J=9.90, 3.00 Hz, 1 H) 7.00 (m, 2 H) 7.26 (m, 2 H) 8.08 (s, 1H).

EXAMPLE 14(33)2-(2-((2R)-5-oxo-2-(4-trifluoromethoxyphenoxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.27 (m, 1 H) 2.44 (m, 1 H) 2.60 (m, 1 H)3.29 (m, 1 H) 3.49 (m, 1 H) 3.73 (m, 1 H) 3.96 (m, 2 H) 4.09 (m, 1 H)4.18 (dd, J=9.90, 3.30 Hz, 1 H) 6.88 (d, J=9.10 Hz, 2 H) 7.16 (d, J=9.10Hz, 2 H) 8.09 (s, 1 H).

EXAMPLE 14(34)2-(2-((2R)-2-(3-(t-butyl)phenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-thiazole-4-carboxylicacid

TLC: Rf 0.48 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.31 (s, 9 H) 1.97 (m, 1 H) 2.25 (m, 1 H) 2.43 (m, 1 H)2.61 (m, 1 H) 3.29 (m, 1 H) 3.52 (m, 1 H) 3.78 (m, 1 H) 3.96 (m, 2 H)4.08 (m, 1 H) 4.18 (dd, J=9.30, 3.00 Hz, 1 H) 6.69 (dd, J=7.70, 2.40 Hz,1 H) 6.90 (m, 1 H) 7.04 (m, 1 H) 7.22 (d, J=7.70 Hz, 1 H) 8.08 (s, 1 H).

EXAMPLE 14(35)2-(2-((2R)-2-(4-chlorophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.25 (m, 1 H) 2.43 (m, 1 H) 2.60 (m, 1 H)3.29 (m, 1 H) 3.49 (m, 1 H) 3.71 (m, 1 H) 3.94 (m, 2 H) 4.08 (m, 1 H)4.20 (dd, J=9.90, 3.00 Hz, 1 H) 6.82 (d, J=9.10 Hz, 2 H) 7.24 (d, J=9.10Hz, 2 H) 8.09 (s, 1 H).

EXAMPLE 14(36)2-(2-((2R)-2-(2-chloro-5-methylphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.40 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.91 (m, 1 H) 2.29 (m, 1 H) 2.33 (s, 3 H) 2.45 (m, 1 H)2.66 (m, 1 H) 3.30 (m, 1 H) 3.58 (m, 1 H) 3.86 (m, 1 H) 4.02 (m, 2 H)4.18 (m, 2 H) 6.74 (m, 2 H) 7.24 (d, J=8.10 Hz, 1 H) 8.07 (s, 1 H).

EXAMPLE 14(37)2-(2-((2R)-2-(3-chloro-5-methoxyphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.43 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.95 (m, 1 H) 2.25 (m, 1 H) 2.43 (m, 1 H) 2.59 (m, 1 H)3.27 (m, 1 H) 3.49 (m, 1 H) 3.72 (m, 1 H) 3.77 (s, 3 H) 3.92 (m, 2 H)4.06 (m, 1 H) 4.18 (dd, J=9.90, 3.00 Hz, 1 H) 6.32 (t, J=2.00 Hz, 1 H)6.50 (t, J=2.00 Hz, 1 H) 6.54 (t, J=2.00 Hz, 1 H) 8.09 (s, 1 H).

EXAMPLE 14(38)2-(2-((2R)-2-(2-acetyl-4-chloro-5-methylphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.48 (chloroform:methanol:acetic acid=90: 10:1);

NMR (CDCl₃): δ 2.02 (m, 1 H) 2.38 (s, 3 H) 2.43 (m, 3 H) 2.54 (s, 3 H)3.32 (m, 1 H) 3.48 (m, 1 H) 3.69 (m, 1 H) 3.99 (m, 1 H) 4.15 (m, 2 H)4.27 (m, 1 H) 6.86 (s, 1 H) 7.68 (s, 1 H) 8.08 (s, 1 H).

EXAMPLE 14(39)2-(2-((2R)-2-(3-methoxyphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.14 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.22 (m, 1 H) 2.42 (m, 1 H) 2.58 (m, 1 H)3.27 (m, 1 H) 3.48 (m, 1 H) 3.75 (m, 4 H) 3.96 (m, 2 H) 4.13 (m, 2 H)6.48 (m, 3 H) 7.17 (t, J=8.24 Hz, 1 H) 8.06 (s, 1 H).

EXAMPLE 14(40)2-(2-((2R)-2-(3-ethoxyphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.13 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 1.34 (t, J=7.14 Hz, 3 H) 1.88 (m, 1 H) 2.19 (d, J=6.96Hz, 1 H) 2.36 (m, 1 H) 2.50 (dd, J=10.07, 6.77 Hz, 1 H) 3.21 (m, 1 H)3.44 (m, 1 H) 3.92 (m, 7 H) 6.38 (m, 2 H) 6.47 (dd, J=8.06, 2.20 Hz, 1H) 7.11 (t, J=8.24 Hz, 1 H) 8.02 (s, 1 H).

EXAMPLE 14(41)2-(2-((2R)-2-(3-difluoromethoxyphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.08 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 2.03 (m, 1 H) 2.24 (m, 1 H) 2.42 (s, 1 H) 2.58 (s, 1 H)3.26 (m, 1 H) 3.48 (m, 1 H) 3.71 (m, 1 H) 4.07 (m, 4 H) 6.60 (m, 4 H)7.25 (m, 1 H) 8.07 (s, 1 H).

EXAMPLE 14(42)2-(2-((2R)-5-oxo-2-(3-(1,1,2,2-tetrafluoroethoxy)phenoxymethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.11 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 2.00 (m, 1 H) 2.42 (m, 3 H) 3.28 (m, 1 H) 3.48 (m, 1 H)3.71 (s, 1 H) 4.00 (m, 3 H) 4.22 (dd, J=9.79, 3.02 Hz, 1 H) 5.89 (m, 1H) 6.81 (m, 3 H) 7.27 (m, 1 H) 8.08 (s, 1 H).

EXAMPLE 14(43)(15α,13E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-17-(3,4-dichlorophenyl)-1,2,3,4,18,19,20-heptanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.38 (chloroform:methanol:acetic acid=50:10:1);

NMR (CD₃OD): δ 1.74 (m, 3H), 2.29 (m, 3H), 2.64 (m, 2H), 3.36 (m, 3H),3.78 (m, 1H), 4.03 (m, 1H), 4.28 (m, 1H), 5.52 (m, 1H), 5.80 (m, 1H),7.10 (dd, J=8.06, 2.20 Hz, 1H), 7.34 (d, J=2.20 Hz, 1H), 7.39 (d, J=8.06Hz, 1H), 8.06 (s,1H).

EXAMPLE 14(44)2-(2-((2R)-2-(3-aminophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.16 (methylene chloride:methanol:acetic acid=18:2:1);

NMR (CDCl₃): δ 1.90 (m, 1 H) 2.16 (m, 1 H) 2.35 (m, 1 H) 2.51 (m, 1 H)3.20 (m, 1 H) 3.44 (m, 1 H) 3.89 (m, 7 H) 6.23 (m, 3 H) 6.99 (t, J=8.06Hz, 1 H) 7.99 (s, 1 H).

EXAMPLE 14(45)2-(2-((2R)-2-(3-methylaminophenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.09 (methylene chloride:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.23 (m, 1 H) 2.41 (m, 1 H) 2.57 (m, 1 H)2.82 (s, 3 H) 3.25 (m, 1 H) 3.50 (m, 1 H) 3.96 (m, 6 H) 6.14 (t, J=2.29Hz, 1 H) 6.25 (m, 2 H) 7.08 (t, J=8.06 Hz, 1 H) 8.06 (s, 1 H).

EXAMPLE 14(46)2-(2-((2R)-2-(3-amino-2-methylphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.15 (methylene chloride:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.98 (m, 4 H) 2.27 (m, 1 H) 2.44 (m, 1 H) 2.60 (m, 1 H)3.23 (m, 1 H) 3.51 (m, 1 H) 4.00 (m, 7 H) 6.28 (d, J=8.06 Hz, 1 H) 6.38(d, J=8.06 Hz, 1 H) 6.96 (t, J=7.87 Hz, 1 H) 8.06 (s, 1 H).

EXAMPLE 14(47)2-(2-((2R)-2-(3-amino-4-methylphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.20 (methylene chloride:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.92 (m, 1 H) 2.09 (s, 3 H) 2.22 (m, 1 H) 2.40 (m, 1 H)2.55 (m, 1 H) 3.24 (m, 1 H) 3.49 (m, 1 H) 3.97 (m, 7 H) 6.22 (m, 2 H)6.93 (d, J=7.87 Hz, 1 H) 8.06 (s, 1 H).

EXAMPLE 14(48)(15α,13E)-15-hydroxy-5-(4-carboxythiazol-2-yl)-9-oxo-17-(naphthalen-2-yl)-1,2,3,4,18,19,20-heptanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.39 (chloroform:methanol:acetic acid=50:10:1);

NMR (CD₃OD): δ 2.02 (m, 7 H), 2.82 (m, 2 H), 3.21 (m, 2 H), 3.72 (m, 1H), 4.13 (m, 2 H), 5.47 (m, 1 H), 5.78 (m, 1 H), 7.36 (m, 4 H), 7.60 (m,1 H), 7.78 (m, 3 H).

EXAMPLE 14(49)2-(2-((2R)-2-(3-aminomethylphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.02 (methylene chloride:methanol=9:1);

NMR (DMSO-D6): δ 1.93 (m, 1H) 2.36 (m, 3 H) 3.34 (m, 7 H) 3.97 (s, 2 H)4.13 (d, J=2.93 Hz, 1 H) 4.60 (dd, J=10.44, 3.48 Hz, 1 H) 6.84 (dd,J=8.24, 2.38 Hz, 1 H) 6.92 (d, J=7.32 Hz, 1 H) 7.21 (m, 1 H) 7.60 (s, 1H) 7.72 (s, 1 H).

EXAMPLE 14(50)2-(2-((2R)-2-(3-dimethylaminomethylphenoxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.17 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 2.04 (m, 1 H) 2.33 (m, 3 H) 2.67 (s, 6 H) 3.07 (m, 1 H)3.68 (m, 5 H) 4.09 (m, 1 H) 4.29 (m, 2 H) 6.75 (d, J=7.32 Hz, 1 H) 6.88(dd, J=7.87, 2.01 Hz, 1 H) 7.18 (m, 1 H) 7.53 (s, 1 H) 7.81 (s, 1 H).

EXAMPLE 14(51)2-(2-((2R)-2-(3,5-dichlorobenzyloxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.09 (methylene chloride:methanol=9:1);

NMR (DMSO-D6): δ 1.74 (m, 1 H) 1.97 (m, 1H) 2.20 (m, 2 H) 3.43 (m, 4 H)3.75 (m, 3 H) 4.53 (s, 2 H) 7.34 (s, 2 H) 7.50 (s, 1 H) 7.88 (s, 1 H).

EXAMPLE 14(52)2-(2-((2S)-2-(2-(3,5-dichlorophenyl)ethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.44 (methylene chloride:methanol:acetic acid=9:1:0.1);

NMR (CDCl₃): δ 1.68 (m, 2 H) 2.29 (m, 6 H) 3.32 (m, 3 H) 3.63 (m, 1 H)3.90 (m, 1 H) 7.01 (d, J=2.20 Hz, 2 H) 7.16 (t, J=2.01 Hz, 1 H) 8.03 (s,1 H).

REFERENCE EXAMPLE 12(5R)-5-(t-butoxydimethylsilyloxymethyl)pyrrolidin-2-one

Under an atmosphere of argon, to a solution of(5R)-5-hydroxymethylpyrrolidin-2-one (15.0 g) in dimethylformamide (130mL) were added imidazole (10.6 g) and t-butyidimethylsilyl chloride(20.5 g) and the mixture was stirred at room temperature for 3 hours.The reaction solution was poured into ice and extracted with ethylacetate. The organic layer was washed with water and brine, dried overanhydrous magnesium sulfate and concentrated to give the title compound(33.0 g) having the following physical data.

TLC: Rf 0.71 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 0.06 (s, 6 H) 0.89 (s, 9 H) 1.73 (m, 1 H) 2.17 (m, 1 H)2.35 (m, 2 H), 3.44 (dd, J=10.20, 7.80 Hz, 1 H) 3.63 (dd, J=10.20, 3.90Hz, 1 H) 3.76 (m, 1 H) 5.76 (br. s., 1 H).

REFERENCE EXAMPLE 13((2R)-2-(t-butoxydimethylsilyloxymethyl)-5-oxopyrrolidin-1-yl)aceticacid ethyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 12 (33.0 g) in anhydrous tetrahydrofuran (300 mL) wasadded potassium t-butoxide (16.0 g) in ice bath and the mixture wasstirred for 10 minutes. Bromoethyl acetate (15.9 mL) was added dropwiseto the reaction solution, which was stirred at room temperatureovernight. An aqueous saturated ammonium chloride solution was added tothe reaction solution, which was extracted with ethyl acetate. Theobtained organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated to give the title compound (41.0 g)having the following physical data.

TLC: Rf 0.73 (ethyl acetate).

REFERENCE EXAMPLE 14(5R)-1-(2-hydroxyethyl)-5-(t-butoxydimethylsilyloxymethy!)pyrrolidin-2-one

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 13 (41.0 g) in tetrahydrofuran-ethanol (9:1, 300 mL)was added sodium borohydride (14.7 g) and the mixture was stirred atroom temperature for 6 hours. The reaction solution was poured intoice—an aqueous saturated ammonium chloride solution and extracted withethyl acetate. The obtained organic layer was washed with water andbrine, dried over anhydrous magnesium sulfate and concentrated to givethe title compound (36.7 g) having the following physical data.

TLC: Rf 0.29 (ethyl acetate).

REFERENCE EXAMPLE 15((2R)-2-(t-butoxydimethylsilyloxymethyl)-5-oxopyrrolidin-1-yl)ethylmethanesulfonate

Under an atmosphere of argon, methanesulfonyl chloride (11.1 mL)wasadded dropwise to a solution of the compound prepared in ReferenceExample 14 (36.7 g) and triethylamine (27.1 mL) in methylene chloride(250 mL)in ice bath and the mixture was stirred for 1 hour. Water wasadded to the reaction solution, which was extracted with methylenechloride. The obtained organic layer was washed with hydrochloric acid,water and brine, dried over anhydrous magnesium sulfate and concentratedto give the title compound (45.6 g) having the following physical data.

TLC: Rf 0.53 (ethyl acetate).

REFERENCE EXAMPLE 16S-((2R)-2-(t-butoxydimethylsilyloxymethyl)-5-oxopyrrolidin-1-yl)ethylethanethioate

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 15 (45.6 g) in dimethylformamide (130 mL) was addedpotassium thiosulfate (14.8 g) and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution, whichwas extracted with ethyl acetate. The obtained organic layer was washedwith water and brine, dried over anhydrous magnesium sulfate andconcentrated to give the title compound (39.9 g) having the followingphysical data.

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1).

REFERENCE EXAMPLE 172-(2-((2R)-2-(t-butoxydimethylsilyloxymethyl)-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylicacid ethyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 16 (39.9 g), 2-bromo-1,3-thiazole-4-carboxylic acidethyl ester (30.7 g) and tributylphosphine (2.63 g) in ethanol (260 mL)was added potassium carbonate (26.9 g) in ice bath and the mixture wasstirred at room temperature overnight. Water was added to the reactionsolution, which was extracted with ethyl acetate. The obtained organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated to give the title compound (57.0 g).

TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1).

REFERENCE EXAMPLE 182-(2-((2R)-2-(t-butoxydimethylsilyloxymethyl)-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylicacid butyl ester

To a solution of the compound prepared in Reference Example 17 (57.0 g)in butanol (260 mL) was added potassium carbonate (17.9 g) and themixture was stirred at 80° C. for 4 hours. After cooling, the reactionsolution was filtrated and concentrated. The obtained residue wasdissolved into ethyl acetate. The solution was washed water and brine,dried over anhydrous magnesium sulfate and concentrated to give thetitle compound (64.1 g) having the following physical data.

TLC: Rf 0.39 (n-hexane:ethyl acetate=1:1).

REFERENCE EXAMPLE 192-(2-((2R)-2-hydroxymethyl-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylicacid butyl ester

To a solution of the compound prepared in Reference Example 18 (64.1 g)in tetrahydrofuran (130 mL) was added a solution of tetrabutylammoniumfluoride (1.0 mol/L) in tetrahydrofuran (130 mL) and the mixture wasstirred at room temperature overnight. Water was added to the reactionsolution, which was extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was purified by column chromatographyon silica gel (ethyl acetate-hexane) to give the title compound (24.0 g)having the following physical data.

TLC: Rf 0.19 (ethyl acetate);

NMR (CDCl₃): δ 0.97 (t, J=7.30 Hz, 3 H) 1.45 (m, 2 H) 1.74 (m, 2 H) 1.90(m, 1 H) 2.13 (m, 1 H) 2.40 (m, 2 H) 3.32 (t, J=5.50 Hz, 1 H) 3.43 (m, 1H) 3.56 (m, 1 H) 3.80 (m, 5 H) 4.33 (t, J=6.70 Hz, 2 H) 7.99 (s, 1 H).

REFERENCE EXAMPLE 202-(2-((2R)-2-formyl-5-oxopyrrolidin-1-yl)ethylthio-1,3-thiazole-4-carboxylicacid butyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 19 (205 mg) and triethylamine (0.48 mL) in ethylacetate(4 mL) were added dimethylsulfoxide (2 mL) and sulfur trioxidepyridine complex (273 mg) at 10° C. and the mixture was stirred at 10 to20° C. for 2 hours. Water was added to the reaction solution, which wasextracted with ethyl acetate. The obtained organic layer was washed withhydrochloric acid, water and brine, dried over anhydrous magnesiumsulfate and concentrated to give the title compound (219 mg) having thefollowing physical data.

TLC: Rf 0.26 (ethyl acetate);

NMR (CDCl₃): δ 0.98 (t, J=7.60 Hz, 3 H) 1.58 (m, 5 H) 2.25 (m, 3 H) 3.43(m, 2 H) 4.03 (m, 2 H) 4.32 (t, J=6.70 Hz, 2 H) 4.64 (m, 1 H) 8.00 (s, 1H) 9.69 (d, J=1.10 Hz, 1 H).

EXAMPLE 152-(2-((2R)-2-heptylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 20 (120 mg) in methylene chloride (3 mL) was addedn-heptylamine (98 μL) and the mixture was stirred at room temperaturefor 1 hour. Sodium triacetoxyborohydride (140 mg) was added to thereaction solution, which was stirred at room temperature for 2 hours. Anaqueous saturated sodium bicarbonate solution was added to the reactionmixture, which was extracted with methylene chloride. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue was purified by column chromatographyon silica gel (ethyl acetate→ethyl acetate:methanol=9:1) to give thecompound of the present invention (119 mg) having the following physicaldata.

TLC: Rf 0.14 (ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ 0.88 (t, J=6.90 Hz, 3 H) 0.97 (t, J=7.40 Hz, 3 H) 1.26(m, 8 H) 1.43 (m, 4 H) 1.74 (m, 2 H) 1.89 (m, 1 H) 2.12 (m, 1 H) 2.30(ddd, J=16.90, 9.90, 5.60 Hz, 1 H) 2.45 (ddd, J=17.20, 10.00, 7.20 Hz, 1H) 2.57 (m, 2 H) 2.78 (m, 2 H) 3.47 (m, 3 H) 3.87 (m, 2 H) 4.33 (t,J=6.77 Hz, 2 H) 8.00 (s, 1 H).

EXAMPLE 15(1) TO 15(10)

By the same procedure as described in Example 15, using a correspondingamine derivative instead of n-heptylamine, the following compounds ofthe present invention were obtained.

EXAMPLE 15(1)2-(2-((2R)-2-(3,5-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.63 (ethyl acetate);

NMR (CDCl₃): δ 0.96 (t, J=7.28 Hz, 3 H) 1.43 (m, 2 H) 1.72 (m, 2 H) 1.88(m, 1 H) 2.36 (m, 3 H) 3.32 (m, 3 H) 3.55 (m, 2 H) 3.94 (m, 1 H) 4.10(m, 1 H) 4.31 (t, J=6.46 Hz, 2 H) 4.73 (m, 1 H) 6.45 (d, J=1.79 Hz, 2 H)6.64 (t, J=1.79 Hz, 1 H) 8.01 (s, 1 H).

EXAMPLE 15(2)2-(2-((2R)-5-oxo-2-(piperidin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.29 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 0.97 (t, J=7.50 Hz, 2 H) 1.44 (m, 8 H) 1.72 (m, 3 H) 2.07(m, 1 H) 2.26 (m, 4 H) 2.41 (m, 4 H) 3.50 (t, J=6.59 Hz, 2 H) 3.67 (m, 1H) 3.92 (m, 2 H) 4.33 (t, J=6.77 Hz, 2 H) 8.01 (s, 1 H).

EXAMPLE 15(3)2-(2-((2R)-2-(morpholin-4-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.51 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 0.97 (t, J=7.41 Hz, 3 H) 1.45 (m, 2 H) 1.74 (m, 3 H) 2.10(m, 1 H) 2.32 (m, 5 H) 2.51 (m, 3 H) 3.51 (t, J=7.05 Hz, 2 H) 3.65 (m, 5H) 3.96 (m, 2 H) 4.33 (t, J=6.77 Hz, 2 H) 8.00 (s, 1 H).

EXAMPLE 15(4)2-(2-((2R)-2-(4-methylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.27 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 0.97 (t, J=7.41 Hz, 3 H) 1.45 (m, 2 H) 1.73 (m, 3 H) 2.08(m, 1 H) 2.25 (s, 3 H) 2.45 (m, 12 H) 3.51 (t, J=6.68 Hz, 2 H) 3.66 (m,1 H) 3.93 (m, 2 H) 4.33 (t, J=6.77 Hz, 2 H) 8.01 (s, 1 H).

EXAMPLE 15(5)2-(2-((2R)-2-(4-(t-butoxycarbonyl)piperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.37 (ethyl acetate);

NMR (CDCl₃): δ 0.97 (t, J=7.50 Hz, 3 H) 1.45 (m, 2 H) 1.45 (s, 9 H) 1.74(m, 3 H) 2.11 (m, 1 H) 2.40 (m, 8 H) 3.35 (t, J=4.94 Hz, 4 H) 3.50 (t,J=6.87 Hz, 2 H) 3.63 (m, 1 H) 3.95 (m, 2 H) 4.33 (t, J=6.77 Hz, 2 H)8.01 (s, 1 H).

EXAMPLE 15(6)2-(2-((2R)-2-(4-benzylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.08 (ethyl acetate);

NMR (CDCl₃): δ 0.96 (t, J=7.41 Hz, 3 H) 1.44 (m, 2 H) 1.71 (m, 3 H) 2.09(m, 1 H) 2.40 (m, 12 H) 3.45 (s, 2 H) 3.50 (t, J=6.77 Hz, 2 H) 3.67 (m,1 H) 3.91 (m, 2 H) 4.30 (t, J=6.77 Hz, 2 H) 7.28 (m, 5 H) 8.00 (s, 1 H).

EXAMPLE 15(7)2-(2-((2R)-2-(cyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.44 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 0.99 (m, 5 H) 1.21 (m, 4 H) 1.49 (m, 4 H) 1.81 (m, 5 H)2.13 (m, 1 H) 2.38 (m, 3 H) 2.79 (d, J=5.13 Hz, 2 H) 3.47 (m, 3 H) 3.87(m, 2 H) 4.33 (t, J=6.59 Hz, 2 H) 8.00 (s, 1 H).

EXAMPLE 15(8)2-(2-((2R)-2-benzylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.36 (ethyl acetate:methanol=9:1);

NMR (CDCl₃): δ 0.96 (t, J=7.30 Hz, 3 H) 1.44 (m, 2 H) 1.72 (m, 2 H) 1.96(m, 1 H) 2.22 (m, 2 H) 2.46 (m, 1 H) 2.90 (m, 2 H) 3.43 (m, 3 H) 3.90(m, 4 H) 4.29 (t, J=6.70 Hz, 2 H) 7.29 (m, 5 H) 7.97 (s, 1 H).

EXAMPLE 15(9)2-(2-((2R)-2-(N-cyclohexyl-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.59 (ethyl acetate:methanol=4:1);

NMR (CDCl₃): δ 0.97 (t, J=7.51 Hz, 3 H) 1.15 (m, 5 H) 1.45 (m, 2 H) 1.72(m, 8 H) 2.06 (m, 1 H) 2.20 (s, 3 H) 2.28 (m, 2 H) 2.41 (m, 2 H) 2.53(dd, J=12.90, 6.30 Hz, 1 H) 3.49 (t, J=6.68 Hz, 2 H) 3.63 (dt, J=13.73,6.68 Hz, 1H) 3.80 (m, 1 H) 3.95 (dt, J=13.73, 6.68 Hz, 1 H) 4.33 (t,J=6.77 Hz, 2 H) 8.01 (s, 1 H).

EXAMPLE 15(10)2-(2-((2R)-2-(N-benzyl-N-cyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid butyl ester

TLC: Rf 0.76 (ethyl acetate);

NMR (CDCl₃): δ 0.97 (t, J=7.32 Hz, 3 H) 1.17 (m, 5 H) 1.45 (m, 2 H) 1.78(m, 8 H) 1.96 (m, 1 H) 2.21 (m, 2 H) 2.40 (m, 2 H) 2.69 (dd, J=13.18,5.13 Hz, 1 H) 3.45 (m, 5 H) 3.6 4 (d, J=13.80 Hz, 1 H) 3.85 (m, 1 H)4.31 (t, J=6.68 Hz, 2 H) 7.24 (m, 5 H) 7.97 (s, 1 H).

EXAMPLE 16(1) TO 16(61)

By the same procedure as described in Example 2, using the compoundprepared in Example 15, 15(1) to 15(10) or a corresponding ester insteadof the compound prepared in Example 1, the following compounds of thepresent invention were obtained.

EXAMPLE 16(1)2-(2-((2R)-2-heptylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.33 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 0.85 (t, J=6.90 Hz, 3 H) 1.25 (m, 8 H) 1.79 (m, 3 H) 2.32(m, 3 H) 2.52 (m, 1 H) 2.91 (dd, J=11.81, 9.34 Hz, 1 H) 3.09 (dd,J=9.34, 7.32 Hz, 2 H) 3.32 (m, 2 H) 3.58 (m, 1 H) 3.74 (m, 2 H) 4.39 (m,1 H) 7.88 (s, 1 H).

EXAMPLE 16(2)2-(2-((2R)-2-(3,5-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.40 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.88 (m, 1 H) 2.21 (m, 1H) 2.45 (m, 2 H) 3.42 (m, 5 H)3.61 (br. s., 2 H) 4.00 (m, 2 H) 6.47 (d, J=1.80 Hz, 2 H) 6.67 (t,J=1.80 Hz, 1 H) 8.10 (s, 1 H).

EXAMPLE 16(3)2-(2-((2R)-2-(N-acetyl-N-(3,5-dichlorophenyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.31 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 1.71 (m, 1 H) 1.96 (s, 3 H) 2.15 (m, 1 H) 2.39 (m, 2 H)3.44 (m, 4 H) 3.95 (m, 2 H) 4.28 (m, 1 H) 7.13 (d, J=1.65 Hz, 2 H) 7.40(t, J=1.65 Hz, 1 H), 8.10 (s, 1 H).

EXAMPLE 16(4)2-(2-((2R)-5-oxo-2-(piperidin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.20 (chloroform:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.51 (m, 2 H) 1.82 (m, 5 H) 2.34 (m, 3 H) 2.65 (dd,J=13.18, 6.77 Hz, 1 H) 2.84 (m, 3 H) 3.08 (dd, J=13.18, 4.03 Hz, 1H)3.47 (m, 4 H) 3.90 (m, 1 H) 4.27 (m, 1 H) 7.98 (s, 1 H).

EXAMPLE 16(5)2-(2-((2R)-2-(morpholin-4-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.28 (chloroform:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.78 (m, 1 H) 2.16 (m, 1 H) 2.51 (m, 8 H) 3.44 (m, 2 H)3.70 (m, 5 H) 3.95 (m, 2 H) 8.08 (s, 1 H).

EXAMPLE 16(6)2-(2-((2R)-2-(4-methylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.07 (chloroform:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.59 (m, 1 H) 2.05 (m, 1 H) 2.23 (m, 1 H) 2.39 (m, 2 H)2.68 (s, 3 H) 2.68 (m, 2 H) 3.06 (m, 7 H) 3.46 (m, 1 H) 3.62 (m, 2 H)3.97 (m, 2 H) 7.89 (s, 1 H).

EXAMPLE 16(7)2-(2-((2R)-2-(4-(t-butoxycarbonyl)piperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.42 (chloroform:methanol:water=40:10:1);

pNMR (CDCl₃): δ 1.47 (s, 9 H) 1.83 (m, 1 H) 2.18 (m, 1 H) 2.53 (m, 8 H)3.43 (m, 6 H) 3.70 (m, 1 H) 3.95 (m, 2 H) 8.08 (s, 1 H).

EXAMPLE 16(8)2-(2-((2R)-2-(4-benzylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.35 (chloroform:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.69 (m, 1H) 2.09 (m, 1 H) 2.35 (m, 3 H) 2.91 (m, 9 H)3.48 (m, 3 H) 3.83 (m, 2 H) 4.00 (d, J=13.18 Hz, 1H) 4.13 (d, J=13.18Hz, 1 H) 7.40 (m, 5 H) 8.07 (s, 1 H).

EXAMPLE 16(9)2-(2-((2R)-2-cyclohexylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.36 (chloroform:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.21 (m, 3 H) 1.59 (m, 3 H) 1.83 (m, 2 H) 2.37 (m, 6 H)2.81 (m, 1 H) 3.26 (m, 3 H) 3.57 (m, 1 H) 3.77 (m, 2 H) 4.44 (m, 1 H)7.88 (s, 1 H).

EXAMPLE 16(10)2-(2-((2R)-2-benzylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.70 (methylene chloride:methanol:water=80:20:1);

NMR (DMSO-D6): δ 1.81 (m, 1 H) 2.07 (m, 2 H) 2.28 (m, 1 H) 2.76 (m, 1 H)2.88 (m, 1 H) 3.34 (m, 3 H) 3.51 (br. s., 2 H) 3.81 (m, 4 H) 7.32 (m, 5H) 8.26 (s, 1 H).

EXAMPLE 16(11)2-(2-((2R)-2-(N-cyclohexyl-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.13 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.09 (m, 1 H) 1.30 (m, 4 H) 1.68 (m, 1 H) 1.92 (m, 5 H)2.36 (m, 3 H) 2.63 (s, 3 H) 2.77 (dd, J=12.90, 8.33 Hz, 1 H) 2.93 (m, 1H) 3.03 (dd, J=12.90, 3.00 Hz, 1 H) 3.42 (m, 3 H) 3.95 (m, 1 H) 4.37 (m,1 H) 7.96 (s, 1 H).

EXAMPLE 16(12)2-(2-((2R)-2-(N-benzyl-N-cyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.29 (ethyl acetate:methanol=4:1);

NMR (CDCl₃): δ 1.19 (m, 5 H) 1.63 (m, 1 H) 1.80 (m, 5 H) 1.99 (m, 1 H)2.26 (m, 2 H) 2.49 (m, J=13.27, 7.23 Hz, 2 H) 2.72 (dd, J=l13.36, 5.49Hz, 1 H) 3.16 (m, 2 H) 3.47 (m, 2 H) 3.61 (d, J=13.20 Hz, 1 H) 3.69 (d,J=13.20 Hz, 1 H) 3.94 (m, 1 H) 7.28 (m, 5 H) 8.05 (s, 1 H).

EXAMPLE 16(13)2-(2-((2R)-2-hexylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.32 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 0.84 (t, J=6.90 Hz, 3 H) 1.29 (m, 6 H) 1.79 (m, 3 H) 2.32(m, 3) 2.51 (m, 1 H) 2.93 (dd, J=11.90, 8.88 Hz, 1 H) 3.09 (dd, J=8.88,7.60 Hz, 2 H) 3.32 (m, 2 H) 3.58 (m, 1 H) 3.74 (m, 2 H) 4.39 (m, 1 H)7.89 (s, 1 H).

EXAMPLE 16(14)2-(2-((2R)-5-oxo-2-(4-phenylpiperidin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.30 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 1.94 (m, 5 H) 2.25 (m, 2 H) 2.55 (m, 5 H) 3.01 (m, 1 H)3.36 (m, 4 H) 3.63 (m, 1 H) 3.92 (m, 1 H) 4.19 (m, 1 H) 7.19 (m, 3 H)7.28 (m, 2 H) 8.01 (s, 1 H).

EXAMPLE 16(15)2-(2-((2R)-2-(4-benzylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.32 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 1.64 (m, 5 H) 1.90 (m, 1 H) 2.32 (m, 5 H) 2.53 (d, J=4.94Hz, 2 H) 2.66 (dd, J=13.09, 7.14 Hz, 1 H) 3.11 (dd, J=13.09, 4.67 Hz, 1H) 3.44 (m, 5 H) 3.89 (dt, J=14.01, 7.09 Hz, 1 H) 4.25 (m, 1 H) 7.10 (m,2 H) 7.24 (m, 3 H) 8.00 (s, 1 H).

EXAMPLE 16(16)2-(2-((2R)-5-oxo-2-(3-phenylpropylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.35 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 2.16 (m, 6 H) 2.45 (m, 1 H) 2.56 (t, J=7.69 Hz, 2 H) 2.93(dd, J=12.36, 8.33 Hz, 1 H) 3.04 (dd, J=9.06, 7.05 Hz, 2 H) 3.22 (m, 1H) 3.34 (m, 1 H) 3.58 (m, 3 H) 4.28 (m, 1 H) 7.04 (m, 2 H) 7.19 (m, 3 H)7.89 (s, 1 H).

EXAMPLE 16(17)2-(2-((2R)-2-((naphthalen-2-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.28 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.98 (s, 1H), 7.77-7.63 (m, 4H), 7.52 (dd, J=8.7, 1.8 Hz,1H), 7.8-7.37 (m, 2H), 4.34 (d, J=133.2 Hz, 1H), 4.26 (m, 1H), 4.10 (d,J=13.2 Hz, 1H), 3.66-3.32 (m, 3H), 3.13 (m, 2H), 2.80 (m, 1H), 2.42-1.98(m, 4H).

EXAMPLE 16(18) 2-(2-((2R)-2-(3,5-dimethylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.19 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.99 (s, 1H), 4.26 (m, 1H), 3.88 (m, 1H), 3.57 (m, 1H),3.85-3.65 (m, 2H), 3.55-3.02 (m, 3H), 2.84 (m, 2H), 2.58 (dd, J=12.9 Hz,6.9 Hz, 1H), 2.50-2.15 (m, 3H), 2.10-1.70 (m; 4H), 0.90 (d, J=6 .3 Hz,3H), 0.88 (d, J=7.5 Hz, 3H), 0.61 (q, J=11.9 Hz, 1H).

EXAMPLE 16(19)2-(2-((2R)-5-oxo-2-(2-phenylethylamino)methyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.25 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.91 (s, 1H), 7.21-7.13 (m, 3H), 7.09-7.01 (m, 2H), 4.35(m, 1H), 3.76-3.47 (m, 3H), 3.44-3.04 (m, 6H), 2.94 (dd, J=12.0, 8.7 Hz,1H), 2.50 (m, 1H), 2.39-2.18 (m, 3H).

EXAMPLE 16(20)2-(2-((2R)-5-oxo-2-(1,2,3,4-tetrahydronaphthalen-1-ylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.37 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 7.96 and 7.69 (each m, 1H), 7.91 and 7.87 (each s, 1H),7.36-7.21 (m, 1H), 7.19-7.00 (m, 1H), 7.19-7.00 and 6.89 (each m, 1H),5.05 and 4.43 (each m, 1H), 4.72-4.55 (m, 1H), 3.86-3.66 (m, 1H), 3.64-3.43 (m, 1H), 3.38-3.10 (m, 3H), 2.90-2.62 (m, 3H), 2.58-1.85 (m, 8H).

EXAMPLE 16(21)2-(2-((2R)-2-(1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.24 (methylene chloride:methanol=9:1);

NMR (CDCl₃): δ 8.00 (s, 1H), 7.24-7.07 (m, 3H), 7.03 (m, 1H), 4.15 (m,1H), 3.94 (m, 1H), 3.91 (d, J=12.0 Hz, 1H), 3.83 (d, J=12.0 Hz, 1H),3.65 (m, 1H), 3.45-3.34 (m, 2H), 3.20-2.85 (m, 5H), 2.70 (dd, J=12.9,6.0 Hz, 1H), 2.54-2.10 (m, 3H), 1.88 (m, 1H).

EXAMPLE 16(22)2-(2-((2R)-2-(2-(3,5-dichlorophenoxy)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid trifluoroacetic acid

TLC: Rf 0.22 (chloroform:methanol:acetic acid=40:10:1);

NMR (CD₃OD): δ 2.02 (m, 1 H) 2.39 (m, 3 H) 3.30 (m, 1 H) 3.58 (m, 6 H)3.84 (m, 1 H) 4.25 (m, 1 H) 4.37 (m, 2 H) 6.93 (d, J=1.74 Hz, 2 H) 7.04(t, J=1.74 Hz, 1 H) 8.23 (s, 1 H).

EXAMPLE 16(23)2-(2-((2R)-5-oxo-2-(3-trifluoromethoxyphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.33 (methylene chloride:methanol:acetic acid=9:1:0.3);

NMR (CDCl₃): δ 1.86 (m, 1 H) 2.14 (m, 1 H) 2.40 (m, 2 H) 3.37 (m, 5 H)3.96 (m, 2 H) 6.37 (s, 1 H) 6.47 (m, 2 H) 7.08 (m, 1 H) 8.04 (s, 1 H).

EXAMPLE 16(24)2-(2-((2R)-2-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.52 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 0.90 (m, 1 H) 0.97 (s, 3 H) 1.17 (s, 3 H) 1.43 (m, 1 H)1.97 (m, 6 H) 2.32 (m, 4 H) 2.52 (m, 2 H) 2.96 (m, 2 H) 3.29 (m, 3 H)3.53 (m, 2 H) 3.80 (m, 1 H) 4.49 (m, 1 H) 7.83 (s, 1 H).

EXAMPLE 16(25)2-(2-((2R)-2-(3-methylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

more polar

TLC: Rf 0.43 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 0.98 (m, 3 H) 1.65 (m, 7 H) 2.11 (m, 2 H) 2.30 (m, 3 H)2.48 (m, 1 H) 2.84 (m, 1 H) 3.54 (m, 6 H) 4.39 (m, 1 H) 7.83 (m, 1 H).

EXAMPLE 16(26)2-(2-((2R)-2-(3-methylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

less polar

TLC: Rf 0.45 (methylene chloride:methanol:water-40:10:1);

NMR (CDCl₃): δ 0.89 (m, 4 H) 1.34 (m, 4 H) 1.68 (m, 1 H) 1.84 (m, 1 H)2.22 (m, 5 H) 2.48 (m, 1 H) 2.81 (m, 1 H) 3.25 (m, 3 H) 3.58 (m, 1H)3.74 (m, 2 H) 4.41 (m 1 H) 7.83 (m, 1 H).

EXAMPLE 16(27)2-(2-((2R)-2-(4-methylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

more polar

TLC: Rf 0.45 (methylene chloride:methanol:water-40:10:1);

NMR (CDCl₃): δ 0.93 (d, J=6.96 Hz, 3 H) 1.55 (m, 4 H) 1.87 (m, 5 H) 2.31(m, 3 H) 2.48 (m, 1 H) 2.88 (m, 1 H) 3.18 (m, 1 H) 3.31 (m, 2 H) 3.57(m, 1 H) 3.74 (m, 2 H) 4.44 (m, 1 H) 7.86 (s, 1 H).

EXAMPLE 16(28)2-(2-((2R)-2-(4-methylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

less polar

TLC: Rf 0.46 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 0.90 (d, J=6.60 Hz, 3 H) 1.00 (m, 2 H) 1.37 (m, 1 H) 1.60(m, 2 H) 1.80 (m, 2 H) 2.24 (m, 5 H) 2.49 (m, 1 H) 2.80 (m, 1 H) 3.19(m, 1 H) 3.30 (m, 2 H) 3.57 (m, 1 H) 3.74 (m, 2 H) 4.41 (m, 1 H) 7.82(s, 1 H).

EXAMPLE 16(29)2-(2-((2R)-2-cyclohexylmethylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.41 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.07 (m, 5 H) 1.76 (m, 6 H) 2.41 (m, 4 H) 2.95 (m, 3 H)3.29 (m, 2 H) 3.52 (m, 1 H) 3.64 (m, 1 H) 3.81 (m, 1 H) 4.50 (m, 1 H)7.85 (s, 1 H).

EXAMPLE 16(30)2-(2-((2R)-2-(indan-1-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.47 (methylene chloride:methanol:water=40:10:1);

NMR (CD₃OD) 6 1.90 (m, 1 H) 2.40 (m, 5 H) 3.33 (m, 8 H) 3.87 (m, 1 H)4.48 (m, 1 H) 7.27 (m, 3 H) 7.54 (d, J=7.2 Hz, 0.4 H) 7.67 (d, J=7.2 Hz,0.6 H) 7.89 (s, 0.6 H) 7.97 (s, 0.4 H).

EXAMPLE 16(31)2-(2-((2R)-5-oxo-2-((tetrahydrofuran-2-ylmethyl)aminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.19 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.50 (m, 1 H) 1.87 (m, 2 H) 2.06 (m, 1 H) 2.38 (m, 4 H)2.97 (m, 2 H) 3.36 (m, 4 H) 3.57 (m, 1 H) 3.81 (m, 3 H) 4.35 (m, 2 H)7.84 (m, 1 H).

EXAMPLE 16(32)2-(2-((2R)-2-(2-methylbenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.43 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 2.08 (m, 1 H) 2.31 (m, 3 H) 2.35 (s, 3 H) 2.76 (m, 1 H)3.21 (m, 2 H) 3.50 (m, 2 H) 3.70 (m, 1 H) 4.00 (d, J=13.60 Hz, 1 H) 4.21(d, J=13.60 Hz, 1 H) 4.38 (m, 1 H) 7.14 (m, 3 H) 7.47 (d, J=7.30 Hz, 1H) 7.91 (s, 1 H).

EXAMPLE 16(33)2-(2-((2R)-2-(2-(1-cyclohexen-1-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.49 (methylene chloride:methanol:water40:10:1);

NMR (CDCl₃): δ 1.53 (m, 4 H) 1.88 (m, 4 H) 2.41 (m, 6 H) 2.93 (m, 1 H)3.19 (m, 2 H) 3.34 (m, 2 H) 3.58 (m, 1 H) 3.73 (m, 2 H) 4.38 (m, 1 H)5.41 (m, 1 H) 7.86 (s, 1 H).

EXAMPLE 16(34)2-(2-((2R)-5-oxo-2-((2R)-2-phenylpropylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.43 (methylene chloride:methanol:water40:10:1);

NMR (CDCl₃): δ 1.34 (d, J=7.00 Hz, 3 H) 2.24 (m, 4 H) 2.59 (m, 1 H) 3.18(m, 6 H) 3.60 (m, 2 H) 4.30 (m, 1 H) 7.13 (m, 2 H) 7.22 (m, 3 H) 7.90(s, 1 H).

EXAMPLE 16(35)2-(2-((2R)-2-(2-(ethylthio)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.32 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.18 (t, J=7.40 Hz, 3 H) 2.30 (m, 3 H) 2.50 (q, J=7.40Hz, 2 H) 2.52 (m, 1 H) 2.91 (m, 2 H) 3.07 (dd, J=12.30, 7.70 Hz, 1H)3.28 (m, 3 H) 3.41 (m, 1 H) 3.68 (m, 3 H) 4.28 (m, 1 H) 7.92 (s, 1 H).

EXAMPLE 16(36)2-(2-((2R)-2-(2-(2-fluorophenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.43 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 2.31 (m, 3 H) 2.53 (m, 1 H) 2.99 (m, 1 H) 3.15 (m, 2 H)3.26 (m, 1 H) 3.38 (m, 3 H) 3.66 (m, 3 H) 4.33 (m, 1 H) 6.94 (m, 2 H)7.06 (m, 1 H) 7.16 (m, 1 H) 7.89 (s, 1 H).

EXAMPLE 16(37)2-(2-((2R)-2-cyclooctylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.49 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 1.51 (m, 8 H) 1.79 (m, 4 H) 2.14 (m, 2 H) 2.31 (m, 2 H)2.48 (m, 1 H) 2.78 (m, 1 H) 3.30 (m, 2 H) 3.52 (m, 3 H) 3.74 (m, 2 H)4.41 (m, 1 H) 7.82 (s, 1 H).

EXAMPLE 16(38)2-(2-((2R)-2-(2,3-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.59 (methylene chloride:methanol:acetic acid=9:1:0.2);

NMR (CDCl₃): δ 1.97 (m, 4 H) 2.19 (m, 4 H) 2.44 (m, 2 H) 3.35 (m, 4 H)3.57 (m, 1 H) 3.98 (m, 2 H) 6.47 (d, J=8.42 Hz, 1H) 6.61 (d, J=7.32 Hz,1 H) 6.99 (t, J=7.87 (s, 1 H) 8.04 (s, 1 H).

EXAMPLE 16(39)2-(2-((2R)-2-(3,4-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.54 (methylene chloride:methanol:acetic acid=9:1:0.2);

NMR (CDCl₃): δ 1.87 (m, 1 H) 2.12 (m, 7 H) 2.38 (m, 2 H) 3.37 (m, 5 H)3.93 (m, 2 H) 6.34 (m, 2 H) 6.88 (d, J=8.06 Hz, 1 H) 8.02 (s, 1 H).

EXAMPLE 16(40)2-(2-((2R)-5-oxo-2-(5,6,7,8-tetrahydronaphthalen-1-ylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.57 (chloroform:methanol:acetic acid=9:1:0.2);

NMR (CDCl₃): δ 1.88 (m, 3 H) 2.35 (m, 5 H) 2.73 (t, J=6.04 Hz, 2 H) 3.38(m, 4 H) 3.59 (m, 1 H) 4.02 (dd, J=8.42, 4.76 Hz, 2 H) 4.02 (m, 2 H)6.44 (d, J=8.06 Hz, 1 H) 6.56 (d, J=6.96 Hz, 1 H) 7.02 (d, J=7.69 Hz, 1H) 8.07 (s, 1 H).

EXAMPLE 16(41)2-(2-((2R)-2-(3-chloro-4-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.47 (chloroform:methanol:acetic acid=9:1:0.2);

NMR (CDCl₃): δ 1.86 (m, 1 H) 2.15 (m, 1 H) 2.39 (m, 2 H) 3.34 (m, 5 H)3.95 (m, 2 H) 6.38 (m, 1 H) 6.55 (dd, J=5.86, 2.93 Hz, 1 H) 6.88 (t,J=8.79 Hz, 1 H) 8.04 (s, 1 H).

EXAMPLE 16(42)2-(2-((2R)-2-(3-chloro-4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.53 (chloroform:methanol:acetic acid=9:1:0.2);

NMR (CDCl₃): δ 1.85 (m, 1 H) 2.13 (m, 4 H) 2.38 (m, 2 H) 3.36 (m, 5 H)3.94 (m, 2 H) 6.36 (dd, J=8.24, 2.38 Hz, 1 H) 6.55 (d, J=2.56 Hz, 1 H)6.93 (d, J=8.42 Hz, 1 H) 8.03 (s, 1 H).

EXAMPLE 16(43)2-(2-((2R)-2-(3,5-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.54 (chloroform:methanol:acetic acid=9:1:0.2);

NMR (CDCl₃): δ 1.89 (m, 1 H) 2.11 (m, 7 H) 2.37 (m, 2 H) 3.30 (m, 4 H)3.50 (m, 1 H) 3.93 (m, 2 H) 6.19 (s, 2 H) 6.35 (s, 1 H) 8.02 (s, 1 H).

EXAMPLE 16(44)2-(2-((2R)-2-(3-bromophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.92 (m, 1 H) 2.21 (m, 1 H) 2.46 (m, 2 H) 3.43 (m, 5 H)4.01 (m, 2 H) 6.54 (m, 1 H) 6.77 (t, J=2.00 Hz, 1 H) 6.86 (m, 1 H) 7.02(t, J=8.10 Hz, 1 H) 8.11 (s, 1 H).

EXAMPLE 16(45)2-(2-((2R)-2-(3,4-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.59 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.91 (m, 1 H) 2.21 (m, 1H) 2.46 (m, 2 H) 3.43 (m, 5 H)4.02 (m, 2 H) 6.47 (dd, J=8.80, 2.80 Hz, 1 H) 6.70 (d, J=2.80 Hz, 1 H)7.19 (d, J=8.80 Hz, 1 H) 8.12 (s, 1 H).

EXAMPLE 16(46)2-(2-((2R)-5-oxo-2-(3-trifluoromethylphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.59 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.20 (m, 1 H) 2.48 (m, 2 H) 3.46 (m, 5 H)4.05 (m, 2 H) 6.79 (m, 2 H) 6.97 (m, 1 H) 7.26 (m, 1 H) 8.11 (s, 1 H).

EXAMPLE 16(47)2-(2-((2R)-2-(4-fluoro-3-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.24 (m, 1 H) 2.48 (m, 2 H) 3.45 (m, 5 H)4.04 (m, 2 H) 6.76 (m, 2 H) 7.01 (t, J=9.30 Hz, 1 H) 8.11 (s, 1 H).

EXAMPLE 16(48)2-(2-((2R)-2-(4-chloro-3-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.92 (m, 1 H) 2.24 (m, 1 H) 2.47 (m, 2 H) 3.45 (m, 5 H)4.03 (m, 2 H) 6.69 (dd, J=8.60, 2.60 Hz, 1 H) 6.89 (d, J=2.60 Hz, 1 H)7.25 (m, 1 H) 8.11 (s, 1 H).

EXAMPLE 16(49)2-(2-((2R)-5-oxo-2-(3,4,5-trichlorophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.90 (m, 1 H) 2.23 (m, 1 H) 2.47 (m, 2 H) 3.45 (m, 5 H)4.01 (m, 2 H) 6.64 (m, 2 H) 8.12 (m, 1 H).

EXAMPLE 16(50)2-(2-((2R)-2-(3-bromo-4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.57 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.93 (m, 1 H) 2.19 (m, 1 H) 2.27 (s, 3 H) 2.46 (m, 2 H)3.43 (m, 5 H) 4.01 (m, 2 H) 6.50 (dd, J=8.40, 2.40 Hz, 1 H) 6.84 (d,J=2.40 Hz, 1 H) 7.01 (d, J=8.40 Hz, 1 H) 8.10 (s, 1 H).

EXAMPLE 16(51)2-(2-((2R)-2-(1-methylhexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.50 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 0.85 (m, 3 H) 1.31 (m, 9 H) 1.56 (m, 1 H) 1.92 (m, 1 H)2.32 (m, 3 H) 2.49 (m, 1 H) 2.76 (m, 1 H) 3.31 (m, 3 H) 3.56 (m, 3 H)3.80 (m, 1 H) 4.46 (m, 1 H) 7.81 (m, 1 H).

EXAMPLE 16(52)2-(2-((2R)-2-(2-ethylhexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.51 (methylene chloride:methanol:water=40: 10:1);

NMR (CDCl₃): δ 0.80 (m, 6 H) 1.27 (m, 9 H) 1.76 (m, 1 H) 2.34 (m, 3 H)2.51 (m, 1 H) 2.99 (m, 3 H) 3.28 (m, 2 H) 3.57 (m, 2 H) 3.80 (m, 1 H)4.54 (m, 1 H) 7.89 (s, 1 H).

EXAMPLE 16(53)2-(2-((2R)-2-octylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.52 (methylene chloride:methanol:water40:10:1);

NMR (CDCl₃): δ 0.85 (t, J=6.90 Hz, 3 H) 1.27 (m, 10 H) 1.79 (m, 2 H)2.33 (m, 3 H) 2.51 (m, 1 H) 2.88 (m, 1 H) 3.09 (m, 2 H) 3.31 (m, 2 H)3.68 (m, 3 H) 4.41 (m, 1 H) 7.82 (s, 1 H).

EXAMPLE 16(54)2-(2-((2R)-2-nonylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.52 (methylene chloride:methanol:water=40:10:1);

NMR (CDCl₃): δ 0.86 (t, J=6.90 Hz, 3 H) 1.25 (m, 12 H) 1.79 (m, 2 H)2.32 (m, 3 H) 2.51 (m, 1 H) 2.90 (m, 1 H) 3.08 (m, 2 H) 3.31 (m, 2 H)3.66 (m, 3 H) 4.40 (m, 1 H) 7.85 (s, 1 H).

EXAMPLE 16(55)2-(2-((2R)-2-((1S)-1-cyclohexylethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.46 (methylene chloride:methanol:water40:10:1);

NMR (CDCl₃): δ 1.08 (m, 5 H) 1.35 (d, J=6.80 Hz, 3 H) 1.72 (m, 6 H) 2.31(m, 3 H) 2.48 (m, 1 H) 2.80 (m, 1 H) 3.29 (m, 3 H) 3.52 (m,1 H) 3.65 (m,1 H) 3.82 (m, 1 H) 4.53 (m, 1 H) 7.83 (s, 1 H).

EXAMPLE 16(56)2-(2-((2R)-2-(adamantan-1-ylmethyl)amino)methyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.49 (methylene chloride:methanol:water40:10:1);

NMR (CDCl₃): δ 1.58 (m, 12 H) 1.86 (m, 3 H) 2.35 (m, 3 H) 2.53 (m, 1 H)2.72 (s, 2 H) 3.23 (m, 3 H) 3.58 (m, 2 H) 3.83 (m, 1 H) 4.66 (m, 1 H)7.94 (s, 1 H).

EXAMPLE 16(57)2-(2-((2R)-2-(3-chloro-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.64 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.97 (m, 1 H) 2.18 (s, 3 H) 2.21 (m, 1 H) 2.48 (m, 2 H)3.39 (m, 4 H) 3.59 (m, 1 H) 4.04 (m, 2 H) 6.51 (d, J=8.00 Hz, 1 H) 6.82(d, J=8.00 Hz, 1 H) 7.03 (t, J=8.00 Hz, 1 H) 8.09 (s, 1 H).

EXAMPLE 16(58)2-(2-((2R)-2-(2,4-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.66 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.25 (m, 1 H) 2.49 (m, 2 H) 3.40 (m, 4 H)3.58 (m, 1 H) 4.01 (m, 2 H) 6.59 (d, J=8.60 Hz, 1 H) 7.11 (dd, J=8.60,2.40 Hz, 1 H) 7.27 (m, 1 H) 8.1 0 (s, 1 H).

EXAMPLE 16(59)2-(2-((2R)-2-(5-chloro-2-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.68 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.94 (m, 1H) 2.23 (m, 1 H) 2.48 (m, 2 H) 3.37 (m, 4 H)3.57 (m, 1 H) 3.81 (s, 3 H) 4.01 (m, 2 H) 6.54 (m, 1 H) 6.65 (m, 2 H)8.08 (s, 1 H).

EXAMPLE 16(60)2-(2-((2R)-2-(4-bromo-3-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.64 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.92 (m, 1 H) 2.22 (m, 1 H) 2.30 (s, 3 H) 2.46 (m, 2 H)3.42 (m, 5 H) 4.01 (m, 2 H) 6.33 (dd, J=8.40, 2.50 Hz, 1 H) 6.50 (d,J=2.50 Hz, 1 H) 7.28 (m, 1 H) 8.1 0 (s, 1 H).

EXAMPLE 16(61)2-(2-((2R)-5-oxo-2-(3-trifluoromethylthiophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.64 (methylene chloride:methanol:acetic acid=80:20:1);

NMR (CDCl₃): δ 1.94 (m, 1 H) 2.23 (m, 1 H) 2.48 (m, 2 H) 3.45 (m, 5 H)4.03 (m, 2 H) 6.71 (m, 1 H) 6.87 (m, 1 H) 7.00 (m, 1 H) 7.20 (t, J=7.80Hz, 1 H) 8.11 (s, 1 H).

EXAMPLE 17(1) TO (345)

By the same procedure as described in Example 15→Example 16, using acorresponding amine derivative instead of n-heptylamine, the followingcompounds of the present invention were obtained. With the proviso that,the following compounds was extracted by reverse extraction process orion-exchange resin.

EXAMPLE 17(1)2-(2-((2R)-2-((naphthalen-1-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.08 minutes;

MASS data (ESI, Pos. 20 V): 442 (M+H)⁺.

EXAMPLE 17(2)2-(2-((2R)-2-(2-(morpholin-4-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.70 minutes;

MASS data (ESI, Pos. 20 V): 415 (M+H)⁺.

EXAMPLE 17(3)2-(2-((2R)-2-(N,N-bis(3-methylbutyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.18 minutes;

MASS data (ESI, Pos. 20 V): 442 (M+H)⁺.

EXAMPLE 17(4)2-(2-((2R)-2-(azocan-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.90 minutes;

MASS data (ESI, Pos. 20 V): 398 (M+H)⁺.

EXAMPLE 17(5)2-(2-((2R)-2-(N-(2-diethylaminoethyl)-N-ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.78 minutes;

MASS data (ESI, Pos. 20 V): 429 (M+H)⁺.

EXAMPLE 17(6)2-(2-((2R)-5-oxo-2-(piperidin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.79 minutes;

MASS data (ESI, Pos. 20 V): 370 (M+H)⁺.

EXAMPLE 17(7)2-(2-((2R)-2-(cyclobutylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.80 minutes;

MASS data (ESI, Pos. 20 V): 356 (M+H)⁺.

EXAMPLE 17(8)2-(2-((2R)-2-((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-ylmethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.18 minutes;

MASS data (ESI, Pos. 20 V): 438 (M+H)⁺.

EXAMPLE 17(9)2-(2-((2R)-2-cyclopentylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.85 minutes;

MASS data (ESI, Pos. 20 V): 370 (M+H)⁺.

EXAMPLE 17(10)2-(2-((2R)-2-(2-methylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 398 (M+H)⁺.

EXAMPLE 17(11)2-(2-((2R)-2-(3-methylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.00 minutes;

MASS data (ESI, Pos. 20 V): 398 (M+H)⁺.

EXAMPLE 17(12)2-(2-((2R)-2-(4-methylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.00 minutes;

MASS data (ESI, Pos. 20 V): 398 (M+H)⁺.

EXAMPLE 17(13)2-(2-((2R)-2-cyclohexylmethylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.03 minutes;

MASS data (ESI, Pos. 20 V): 398 (M+H)⁺.

EXAMPLE 17(14)2-(2-((2R)-2-(2-(1-methylpyrrolidin-2-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.69 minutes;

MASS data (ESI, Pos. 20 V): 413 (M+H)⁺.

EXAMPLE 17(15)2-(2-((2R)-2-(1-ethylpyrrolidin-2-ylmethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.70 minutes;

MASS data (ESI, Pos. 20 V): 413 (M+H)⁺.

EXAMPLE 17(16)2-(2-((2R)-2-(furan-2-ylmethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.85 minutes;

MASS data (ESI, Pos. 20 V): 382 (M+H)⁺.

EXAMPLE 17(17)2-(2-((2R)-2-(indan-1-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 418 (M+H)⁺.

EXAMPLE 17(18)2-(2-((2R)-2-(N-(2-propenyl)-N-cyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.97 minutes;

MASS data (ESI, Pos. 20 V): 424 (M+H)⁺.

EXAMPLE 17(19)2-(2-((2R)-2-cycloheptylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 398 (M+H)⁺.

EXAMPLE 17(20)2-(2-((2R)-5-oxo-2-(1,2,3,4-tetrahydro-β-carbolin-2-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.04 minutes;

MASS data (ESI, Pos. 20 V): 457 (M+H)⁺.

EXAMPLE 17(21)2-(2-((2R)-5-oxo-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.74 minutes;

MASS data (ESI, Pos. 20 V): 356 (M+H)⁺.

EXAMPLE 17(22)2-(2-((2R)-5-oxo-2-(tetrahydrofuran-2-ylmethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.81 minutes;

MASS data (ESI, Pos. 20 V): 386 (M+H)⁺.

EXAMPLE 17(23)2-(2-((2R)-2-(2-(indol-3-yl)-1-methylethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.06 minutes;

MASS data (ESI, Pos. 20 V): 459 (M+H)⁺.

EXAMPLE 17(24)2-(2-((2R)-2-(N-(2-(indol-3-yl)ethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.05 minutes;

MASS data (ESI, Pos. 20 V): 459 (M+H)⁺.

EXAMPLE 17(25)2-(2-((2R)-5-oxo-2-(4-phenylpiperazin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.02 minutes;

MASS data (ESI, Pos. 20 V): 447 (M+H)⁺.

EXAMPLE 17(26)2-(2-((2R)-2-(4-hydroxy-4-phenylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.95 minutes;

MASS data (ESI, Pos. 20 V): 462 (M+H)⁺.

EXAMPLE 17(27)2-(2-((2R)-5-oxo-2-(pyridin-2-ylmethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.83 minutes;

MASS data (ESI, Pos. 20 V): 393 (M+H)⁺.

EXAMPLE 17(28)2-(2-((2R)-5-oxo-2-(2-(pyridin-2-yl)ethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.71 minutes;

MASS data (ESI, Pos. 20 V): 407 (M+H)⁺.

EXAMPLE 17(29)2-(2-((2R)-5-oxo-2-(pyridin-3-ylmethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.66 minutes;

MASS data (ESI, Pos. 20 V): 393 (M+H)⁺.

2-(2-((2R)-5-oxo-2-(pyridin-4-ylmethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.65 minutes;

MASS data (ESI, Pos. 20 V): 393 (M+H)⁺.

2-(2-((2R)-2-(1-ethoxycarbonylpiperidin-4-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.93 minutes;

MASS data (ESI, Pos. 20 V): 457 (M+H)⁺.

EXAMPLE 17(32)2-(2-((2R)-5-oxo-2-(2-(piperidin-1-yl)ethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.73 minutes;

MASS data (ESI, Pos. 20 V): 413 (M+H)⁺.

EXAMPLE 17(33)2-(2-((2R)-2-(perhydroquinolin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.97 minutes;

MASS data (ESI, Pos. 20 V): 424 (M+H)⁺.

EXAMPLE 17(34)2-(2-((2R)-2-(t-butylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.80 minutes;

MASS data (ESI, Pos. 20 V): 358 (M+H)⁺.

EXAMPLE 17(35)

2-(2-((2R)-5-oxo-2-(1-phenylethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(36)2-(2-((2R)-2-(1,2-dimethylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.88 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(37)2-(2-((2R)-2-(2-methoxy-1-methylethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.80 minutes;

MASS data (ESI, Pos. 20 V): 374 (M+H)⁺.

EXAMPLE 17(38)2-(2-((2R)-2-(1,3-dimethylbutylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 386 (M+H)⁺.

EXAMPLE 17(39)2-(2-((2R)-2-(1-methylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.83 minutes;

MASS data (ESI, Pos. 20 V): 358 (M+H)⁺.

EXAMPLE 17(40) 2-(2-((2R)-2-(l-ethylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.88 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(41)2-(2-((2R)-2-(1-methylbutylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time 2.93 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(42)2-(2-((2R)-2-(2-methoxybenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.97 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(43)2-(2-((2R)-2-(2-methylbenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.99 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(44)2-(2-((2R)-2-(3-methoxybenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.97 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(45)2-(2-((2R)-2-(4-chlorobenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.04 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(46)2-(2-((2R)-2-(4-methoxybenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(47)2-(2-((2R)-2-(4-methylbenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.00 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(48)2-(2-((2R)-2-(2,2-dimethylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.91 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(49)2-(2-((2R)-2-(2-methylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.83 minutes;

MASS data (ESI, Pos. 20 V): 358 (M+H)⁺.

EXAMPLE 17(50)2-(2-((2R)-2-(2-fluoroethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.70 minutes;

MASS data (ESI, Pos. 20 V): 348 (M+H)⁺.

EXAMPLE 17(51)2-(2-((2R)-2-(2-phenylaminoethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.01 minutes;

MASS data (ESI, Pos. 20 V): 421 (M+H)⁺.

EXAMPLE 17(52)2-(2-((2R)-2-(N-(2-diethylaminoethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.73 minutes;

MASS data (ESI, Pos. 20 V): 415 (M+H)⁺.

EXAMPLE 17(53)2-(2-((2R)-2-(2-methoxyethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.77 minutes;

MASS data (ESI, Pos. 20 V): 360 (M+H)⁺.

EXAMPLE 17(54)2-(2-((2R)-2-(2-(4-methylphenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.09 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(55)2-(2-((2R)-2-(4-phenylbutylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.16 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(56)2-(2-((2R)-2-(pentylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.97 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(57)2-(2-((2R)-2-(N-benzyl-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.94 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(58)2-(2-((2R)-2-(N-methyl-N-(2-phenylethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.02 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(59)2-(2-((2R)-2-(N-benzyl-N-isopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(60)2-(2-((2R)-2-(N,N-bis(2-methylpropyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.97 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(61)2-(2-((2R)-2-(N-benzyl-N-ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(62)2-(2-((2R)-2-(N,N-diethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.76 minutes;

MASS data (ESI, Pos. 20 V): 358 (M+H)⁺.

EXAMPLE 17(63)2-(2-((2R)-2-(N-methyl-N-propylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.81 minutes;

MASS data (ESI, Pos. 20 V): 358 (M+H)⁺.

EXAMPLE 17(64)2-(2-((2R)-2-(N,N-dipropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.88 minutes;

MASS data (ESI, Pos. 20 V): 386 (M+H)⁺.

EXAMPLE 17(65)2-(2-((2R)-2-(N-benzyl-N-butylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.08 minutes;

MASS data (ESI, Pos. 20 V): 448 (M+H)⁺.

EXAMPLE 17(66)2-(2-((2R)-2-butylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.88 minutes;

MASS data (ESI, Pos. 20 V): 358 (M+H)⁺.

EXAMPLE 17(67)2-(2-((2R)-2-(2-(1-cyclohexen-1-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.09 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(68)2-(2-((2R)-2-(cyclopropylmethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.82 minutes;

MASS data (ESI, Pos. 20 V): 356 (M+H)⁺.

EXAMPLE 17(69)2-(2-((2R)-2-(4-t-butylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.23 minutes;

MASS data (ESI, Pos. 20 V): 440 (M+H)⁺.

EXAMPLE 17(70)2-(2-((2R)-2-(1-propylbutylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.06 minutes;

MASS data (ESI, Pos. 20 V): 400 (M+H)⁺.

EXAMPLE 17(71)2-(2-((2R)-2-(N-methyl-N-(2-methylpropyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.85 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(72)2-(2-((2R)-2-(N-ethyl-N-propylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.81 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(73)2-(2-((2R)-2-(N-ethyl-N-(pyridin-4-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.78 minutes;

MASS data (ESI, Pos. 20 V): 421 (M+H)⁺.

EXAMPLE 17(74)2-(2-((2R)-2-(2-(N-ethyl-N-(3-methylphenyl))ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.09 minutes;

MASS data (ESI, Pos. 20 V): 463 (M+H)⁺.

EXAMPLE 17(75)2-(2-((2R)-2-(2-(pyridin-4-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.66 minutes;

MASS data (ESI, Pos. 20 V): 407 (M+H)⁺.

EXAMPLE 17(76)2-(2-((2R)-2-(4-t-butylbenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.21 minutes;

MASS data (ESI, Pos. 20 V): 448 (M+H)⁺.

EXAMPLE 17(77)2-(2-((2R)-2-(3-methylthiopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.88 minutes;

MASS data (ESI, Pos. 20 V): 390 (M+H)⁺.

EXAMPLE 17(78)2-(2-((2R)-2-(N-methyl-N-isopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.76 minutes;

MASS data (ESI, Pos. 20 V): 358 (M+H)⁺.

EXAMPLE 17(79)2-(2-((2R)-2-isopropylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.76 minutes;

MASS data (ESI, Pos. 20 V): 344 (M+H)⁺.

EXAMPLE 17(80)2-(2-((2R)-2-(2-(thiophene-2-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 412 (M+H)⁺.

EXAMPLE 17(81)2-(2-((2R)-2-(2-t-butylthioethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.02 minutes;

MASS data (ESI, Pos. 20 V): 418 (M+H)⁺.

EXAMPLE 17(82)2-(2-((2R)-2-(1-benzylpyrrolidin-3-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.86 minutes;

MASS data (ESI, Pos. 20 V): 461 (M+H)⁺.

EXAMPLE 17(83)2-(2-((2R)-2-(N-(2-propenyl)-N-cyclopentylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.89 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(84)2-(2-((2R)-2-(5-methylfuran-2-ylmethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.93 minutes;

MASS data (ESI, Pos. 20 V): 396 (M+H)⁺.

EXAMPLE 17(85)2-(2-((2R)-2-(2-(pyridin-3-yl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.67 minutes;

MASS data (ESI, Pos. 20 V): 407 (M+H)⁺.

EXAMPLE 17(86)2-(2-((2R)-2-((2R)-2-phenylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.02 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(87)2-(2-((2R)-2-(pyrazol-3-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.81 minutes;

MASS data (ESI, Pos. 20 V): 368 (M+H)⁺.

EXAMPLE 17(88)2-(2-((2R)-2-(1,2,3,6-tetrahydropyridin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.76 minutes;

MASS data (ESI, Pos. 20 V): 368 (M+H)⁺.

EXAMPLE 17(89)2-(2-((2R)-2-(2-fluorobenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.93 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(90)2-(2-((2R)-2-(3-fluorobenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(91)2-(2-((2R)-2-(2-phenylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.03 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(92)2-(2-((2R)-2-(2,5-difluorobenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 428 (M+H)⁺.

EXAMPLE 17(93)2-(2-((2R)-2-(1-ethylpyrazol-5-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.80 minutes;

MASS data (ESI, Pos. 20 V): 396 (M+H)⁺.

EXAMPLE 17(94)2-(2-((2R)-2-(2-ethylthioethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.90 minutes;

MASS data (ESI, Pos. 20 V): 390 (M+H)⁺.

EXAMPLE 17(95)2-(2-((2R)-2-(N-(3-dimethylaminopropyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.63 minutes;

MASS data (ESI, Pos. 20 V): 401 (M+H)⁺.

EXAMPLE 17(96)2-(2-((2R)-2-(2-(2-fluorophenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.02 minutes;

MASS data (ESI, Pos. 20 V): 424 (M+H)⁺.

EXAMPLE 17(97)2-(2-((2R)-2-cyclooctylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.06 minutes;

MASS data (ESI, Pos. 20 V): 412 (M+H)⁺.

EXAMPLE 17(98)2-(2-((2R)-2-(3-pyrrolin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.73 minutes;

MASS data (ESI, Pos. 20 V): 354 (M+H)⁺.

EXAMPLE 17(99)2-(2-((2R)-2-(2-methylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.79 minutes;

MASS data (ESI, Pos. 20 V): 384 (M+H)⁺.

EXAMPLE 17(100)2-(2-((2R)-2-(3-methylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.86 minutes;

MASS data (ESI, Pos. 20 V): 384 (M+H)⁺.

EXAMPLE 17(101)2-(2-((2R)-2-(4-methylpiperidin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.86 minutes;

MASS data (ESI, Pos. 20 V): 384 (M+H)⁺.

EXAMPLE 17(102)2-(2-((2R)-2-(3-(morpholin-4-yl)propylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.67 minutes;

MASS data (ESI, Pos. 20 V): 429 (M+H)⁺.

EXAMPLE 17(103)2-(2-((2R)-2-(azepan-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.84 minutes;

MASS data (ESI, Pos. 20 V): 384 (M+H)⁺.

EXAMPLE 17(104)2-(2-((2R)-2-(1,1,3,3-tetramethylbutylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.06 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(105)2-(2-((2R)-2-(1,1-dimethylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.85 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(106)2-(2-((2R)-2-(1-methyl-3-phenylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.10 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(107)2-(2-((2R)-2-(1,5-dimethylhexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.18 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(108)2-(2-((2R)-2-(1-methylhexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.09 minutes;

MASS data (ESI, Pos. 20 V): 400 (M+H)⁺.

EXAMPLE 17(109)2-(2-((2R)-2-(1-methylheptylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.20 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(110)2-(2-((2R)-2-(2-chlorobenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(111)2-(2-((2R)-2-(4-fluorobenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(112)2-(2-((2R)-2-(2-ethylhexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.18 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(113)2-(2-((2R)-2-(2-dimethylaminoethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.65 minutes;

MASS data (ESI, Pos. 20 V): 373 (M+H)⁺.

EXAMPLE 17(114)2-(2-((2R)-2-(2-propynylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.74 minutes;

MASS data (ESI, Pos. 20 V): 340 (M+H)⁺.

EXAMPLE 17(115)2-(2-((2R)-2-(2-propenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.76 minutes;

MASS data (ESI, Pos. 20 V): 342 (M+H)⁺.

EXAMPLE 17(116)2-(2-((2R)-2-(3-methylbutylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.95 minutes;

MASS data (ESI, Pos. 20 V): 372 (M+H)⁺.

EXAMPLE 17(117)2-(2-((2R)-2-(3-dimethylaminopropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.64 minutes;

MASS data (ESI, Pos. 20 V): 387 (M+H)⁺.

EXAMPLE 17(118)2-(2-((2R)-2-(3-ethoxypropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.86 minutes;

MASS data (ESI, Pos. 20 V): 388 (M+H)⁺.

EXAMPLE 17(119)2-(2-((2R)-2-octylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.25 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(120)2-(2-((2R)-2-nonylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.34 minutes;

MASS data (ESI, Pos. 20 V): 428 (M+H)⁺.

EXAMPLE 17(121)2-(2-((2R)-2-(2,6-difluorobenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.93 minutes;

MASS data (ESI, Pos. 20 V): 428 (M+H)⁺.

EXAMPLE 17(122)2-(2-((2R)-2-(3-methoxypropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.81 minutes;

MASS data (ESI, Pos. 20 V): 374 (M+H)⁺.

EXAMPLE 17(123)2-(2-((2R)-2-(3-butoxypropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.05 minutes;

MASS data (ESI, Pos. 20 V): 416 (M+H)⁺.

EXAMPLE 17(124)2-(2-((2R)-2-(N,N-bis(2-methoxyethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.83 minutes;

MASS data (ESI, Pos. 20 V): 418 (M+H)⁺.

EXAMPLE 17(125)2-(2-((2R)-2-(3-chlorobenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.03 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(126)2-(2-((2R)-2-(3-dimethylamino-2,2-dimethylpropylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.69 minutes;

MASS data (ESI, Pos. 20 V): 415 (M+H)⁺.

EXAMPLE 17(127)2-(2-((2R)-2-(4-methyl-1,4-diazepan-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.66 minutes;

MASS data (ESI, Pos. 20 V): 399 (M+H)⁺.

EXAMPLE 17(128)2-(2-((2R)-2-(4-ethylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.75 minutes;

MASS data (ESI, Pos. 20 V): 399 (M+H)⁺.

EXAMPLE 17(129)2-(2-((2R)-2-((1S)-1-cyclohexylethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.06 minutes;

MASS data (ESI, Pos. 20 V): 412 (M+H)⁺.

EXAMPLE 17(130)2-(2-((2R)-2-(5-methylpyrazol-3-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.85 minutes;

MASS data (ESI, Pos. 20 V): 382 (M+H)⁺.

EXAMPLE 17(131)2-(2-((2R)-2-((1R)-1-(4-methylphenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.04 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(132)2-(2-((2R)-2-(1-ethynylcyclohexylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 408 (M+H)⁺.

EXAMPLE 17(133)2-(2-((2R)-2-(2,6-dimethylmorpholin-4-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.81 minutes;

MASS data (ESI, Pos. 20 V): 400 (M+H)⁺.

EXAMPLE 17(134)2-(2-((2R)-2-(N-methyl-N-(2-(pyridin-2-yl)ethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.73 minutes;

MASS data (ESI, Pos. 20 V): 421 (M+H)⁺.

EXAMPLE 17(135)2-(2-((2R)-2-(N-methyl-N-(1-methylpiperidin-4-yl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.61 minutes;

MASS data (ESI, Pos. 20 V): 413 (M+H)⁺.

EXAMPLE 17(136)2-(2-((2R)-2-(1,1-diethyl-2-propynylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.91 minutes;

MASS data (ESI, Pos. 20 V): 396 (M+H)⁺.

EXAMPLE 17(137)2-(2-((2R)-2-(N-ethyl-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.71 minutes;

MASS data (ESI, Pos. 20 V): 344 (M+H)⁺.

EXAMPLE 17(138)2-(2-((2R)-2-(N-ethyl-N-(2-methyl-2-propenyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.78 minutes;

MASS data (ESI, Pos. 20 V): 384 (M+H)⁺.

EXAMPLE 17(139)2-(2-((2R)-2-(1-(4-fluorophenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.01 minutes;

MASS data (ESI, Pos. 20 V): 424 (M+H)⁺.

EXAMPLE 17(140)2-(2-((2R)-2-((1R,2R,4S)-bicyclo[2.2.1]hept-2-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.95 minutes;

MASS data (ESI, Pos. 20 V): 396 (M+H)⁺.

EXAMPLE 17(141)2-(2-((2R)-2-((2S)-2-methoxymethylpyrrolidin-1-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.83 minutes;

MASS data (ESI, Pos. 20 V): 400 (M+H)⁺.

EXAMPLE 17(142)2-(2-((2R)-2-(1,2,4-triazol-4-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.79 minutes;

MASS data (ESI, Pos. 20 V): 369 (M+H)⁺.

EXAMPLE 17(143)2-(2-((2R)-2-(1-methylbenzimidazol-2-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.93 minutes;

MASS data (ESI, Pos. 20 V): 432 (M+H)⁺.

EXAMPLE 17(144)2-(2-((2R)-5-oxo-2-(5-phenylpyrazol-3-ylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.03 minutes;

MASS data (ESI, Pos. 20 V): 444 (M+H)⁺.

EXAMPLE 17(145)2-(2-((2R)-5-oxo-2-(thiophene-2-ylmethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.89 minutes;

MASS data (ESI, Pos. 20 V): 398 (M+H)⁺.

EXAMPLE 17(146)2-(2-((2R)-2-(2-(4-aminosulfonylphenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.85 minutes;

MASS data (ESI, Pos. 20 V): 485 (M+H)⁺.

EXAMPLE 17(147)2-(2-((2R)-2-(adamantan-1-ylmethyl)amino)methyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.18 minutes;

MASS data (ESI, Pos. 20 V): 450 (M+H)⁺.

EXAMPLE 17(148)2-(2-((2R)-2-(4-aminosulfonylbenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.83 minutes;

MASS data (ESI, Pos. 20 V): 471 (M+H)⁺.

EXAMPLE 17(149)2-(2-((2R)-2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.93 minutes;

MASS data (ESI, Pos. 20 V): 478 (M+H)⁺.

EXAMPLE 17(150)2-(2-((2R)-2-(6,7-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.81 minutes;

MASS data (ESI, Pos. 20 V): 464 (M+H)⁺.

EXAMPLE 17(151)2-(2-((2R)-2-(2-(3,4-dihydroxyphenyl)ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.83 minutes;

MASS data (ESI, Pos. 20 V): 438 (M+H)⁺.

EXAMPLE 17(152)2-(2-((2R)-5-oxo-2-(2,2,2-trifluoroethylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.89 minutes;

MASS data (ESI, Pos. 20 V): 384 (M+H)⁺.

EXAMPLE 17(153)2-(2-((2R)-2-(3-methylbenzylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.01 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(154)2-(2-((2R)-2-(1,4′-bipiperidin-1′-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.73 minutes;

MASS data (ESI, Pos. 20 V): 453 (M+H)⁺.

EXAMPLE 17(155)2-(2-((2R)-2-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 505 (M+H)⁺.

EXAMPLE 17(156)2-(2-((2R)-5-oxo-2-(4-(3-trifluoromethylphenyl)piperazin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.22 minutes;

MASS data (ESI, Pos. 20 V): 515 (M+H)⁺.

EXAMPLE 17(157)2-(2-((2R)-2-(4-(4-methoxyphenyl)piperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.01 minutes;

MASS data (ESI, Pos. 20 V): 477 (M+H)⁺.

EXAMPLE 17(158)2-(2-((2R)-5-oxo-2-(4-(4-trifluoromethylphenyl)piperazin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.23 minutes;

MASS data (ESI, Pos. 20 V): 515 (M+H)⁺.

EXAMPLE 17(159)2-(2-((2R)-2-(N-methyl-N-(4-(pyridin-3-yl)butyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.75 minutes;

MASS data (ESI, Pos. 20 V): 449 (M+H)⁺.

EXAMPLE 17(160)2-(2-((2R)-2-(N-methyl-N-(2-(pyridin-4-yl)ethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.68 minutes;

MASS data (ESI, Pos. 20 V): 421 (M+H)⁺.

EXAMPLE 17(161)2-(2-((2R)-2-(N-methyl-N-(pyridin-3-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.73 minutes;

MASS data (ESI, Pos. 20 V): 407 (M+H)⁺.

EXAMPLE 17(162)2-(2-((2R)-2-(N-methyl-N-(6-methylpyridin-2-ylmethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.91 minutes;

MASS data (ESI, Pos. 20 V): 421 (M+H)⁺.

EXAMPLE 17(163)2-(2-((2R)-2-(4-cyclohexylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.91 minutes;

MASS data (ESI, Pos. 20 V): 453 (M+H)⁺.

EXAMPLE 17(164)2-(2-((2R)-2-(4-(3-methoxyphenyl)piperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.05 minutes;

MASS data (ESI, Pos. 20 V): 477 (M+H)⁺.

EXAMPLE 17(165)2-(2-((2R)-2-(4-(2-methoxyphenyl)piperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.02 minutes;

MASS data (ESI, Pos. 20 V): 477 (M+H)⁺.

EXAMPLE 17(166)2-(2-((2R)-2-(4-(2,4-dimethoxyphenyl)piperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.04 minutes;

MASS data (ESI, Pos. 20 V): 507 (M+H)⁺.

EXAMPLE 17(167)2-(2-((2R)-2-(4-(2,4-dimethylphenyl)piperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.21 minutes;

MASS data (ESI, Pos. 20 V): 475 (M+H)⁺.

EXAMPLE 17(168)2-(2-((2R)-5-oxo-2-(4-((2E)-3-phenyl-2-propenyl)piperazin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.07 minutes;

MASS data (ESI, Pos. 20 V): 487 (M+H)⁺.

EXAMPLE 17(169)2-(2-((2R)-5-oxo-2-(4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.84 minutes;

MASS data (ESI, Pos. 20 V): 482 (M+H)⁺.

EXAMPLE 17(170)2-(2-((2R)-2-(4-ethoxycarbonylpiperazin-1-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.89 minutes;

MASS data (ESI, Pos. 20 V): 443 (M+H)⁺.

EXAMPLE 17(171)2-(2-((2R)-5-oxo-2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.01 minutes;

MASS data (ESI, Pos. 20 V): 516 (M+H)⁺.

EXAMPLE 17(172)2-(2-((2R)-5-oxo-2-(4-(5-trifluoromethylpyridin-2-yl)-1,4-diazepan-1-ylmethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.15 minutes;

MASS data (ESI, Pos. 20 V): 530 (M+H)⁺.

EXAMPLE 17(173)2-(2-((2R)-2-(N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 480 (M+H)⁺.

EXAMPLE 17(174)2-(2-((2R)-2-(N-benzyl-N-(2-cyanoethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.18 minutes;

MASS data (ESI, Pos. 20 V): 445 (M+H)⁺.

EXAMPLE 17(175)2-(2-((2R)-2-(N-benzyl-N-(2-dimethylaminoethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.03 minutes;

MASS data (ESI, Pos. 20 V): 463 (M+H)⁺.

EXAMPLE 17(176)2-(2-((2R)-2-(N-(furan-2-ylmethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.88 minutes;

MASS data (ESI, Pos. 20 V): 396 (M+H)⁺.

EXAMPLE 17(177)2-(2-((2R)-2-(N-ethyl-N-(4-hydroxybutyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.77 minutes;

MASS data (ESI, Pos. 20 V): 402 (M+H)⁺.

EXAMPLE 17(178)2-(2-((2R)-2-(N,N-bis(2-ethoxyethyl)aminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.00 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(179)2-(2-((2R)-2-(N-(2-cyanoethyl)-N-ethylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.79 minutes;

MASS data (ESI, Pos. 20 V): 383 (M+H)⁺.

EXAMPLE 17(180)2-(2-((2R)-2-(N-(2-methoxyethyl)-N-methylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.80 minutes;

MASS data (ESI, Pos. 20 V): 374 (M+H)⁺.

EXAMPLE 17(181)2-(2-((2R)-2-(6-methoxy-1,2,3,4-tetrahydro-p-carbolin-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.03 minutes;

MASS data (ESI, Pos. 20 V): 487 (M+H)⁺.

EXAMPLE 17(182)2-(2-((2R)-2-(3,4-dihydropyrido[4,3-b]-1,6-naphthylidin-2-ylmethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.74 minutes;

MASS data (ESI, Pos. 20 V): 470 (M+H)⁺.

EXAMPLE 17(183)2-(2-((2R)-2-phenylaminomethyl-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.20 minutes;

MASS data (ESI, Pos. 20 V): 378 (M+H)⁺.

EXAMPLE 17(184)2-(2-((2R)-2-(2-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.18 minutes;

MASS data (ESI, Pos. 20 V): 408 (M+H)⁺.

EXAMPLE 17(185)2-(2-((2R)-2-(2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.35 minutes;

MASS data (ESI, Pos. 20 V): 392 (M+H)⁺.

EXAMPLE 17(186)2-(2-((2R)-2-(2,3-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.34 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(187)2-(2-((2R)-2-(2,4-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.33 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(188)2-(2-((2R)-2-(2,5-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.43 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(189)2-(2-((2R)-2-(2,6-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.13 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(190)2-(2-((2R)-2-(3-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.26 minutes;

MASS data (ESI, Pos. 20 V): 408 (M+H)⁺.

EXAMPLE 17(191)2-(2-((2R)-2-(3-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.26 minutes;

MASS data (ESI, Pos. 20 V): 392 (M+H)⁺.

EXAMPLE 17(192)2-(2-((2R)-2-(3,4-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.19 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(193)2-(2-((2R)-2-(4-chlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.46 minutes;

MASS data (ESI, Pos. 20 V): 412 (M+H)⁺.

EXAMPLE 17(194)2-(2-((2R)-2-(4-diethylaminophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.93 minutes;

MASS data (ESI, Pos. 20 V): 449 (M+H)⁺.

EXAMPLE 17(195)2-(2-((2R)-2-(4-methylthiophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.38 minutes;

MASS data (ESI, Pos. 20 V): 424 (M+H)⁺.

EXAMPLE 17(196)2-(2-((2R)-2-(4-t-butylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.51 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(197)2-(2-((2R)-2-(4-isopropylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.40 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(198)2-(2-((2R)-2-(4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.16 minutes;

MASS data (ESI, Pos. 20 V): 392 (M+H)⁺.

EXAMPLE 17(199)2-(2-((2R)-2-(2,4-dimethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 438 (M+H)⁺.

EXAMPLE 17(200)2-(2-((2R)-2-(3,4-dimethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 438 (M+H)⁺.

EXAMPLE 17(201)2-(2-((2R)-2-(4-isopropoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.16 minutes;

MASS data (ESI, Pos. 20 V): 436 (M+H)⁺.

EXAMPLE 17(202)2-(2-((2R)-2-(2-t-butylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.71 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(203)2-(2-((2R)-2-(2-fluoro-5-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.46 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(204)2-(2-((2R)-2-(2-chloro-6-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.48 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(205)2-(2-((2R)-2-(4-methoxy-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.09 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(206)2-(2-((2R)-2-(3,5-difluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.46 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(207)2-(2-((2R)-2-(3-ethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.36 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(208)2-(2-((2R)-2-(3-(1-hydroxyethyl)phenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.05 minutes;

MASS data (ESI, Pos. 20 V): 422, 404 (M+H)⁺.

EXAMPLE 17(209)2-(2-((2R)-2-(3-hydroxymethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.00 minutes;

MASS data (ESI, Pos. 20 V): 408 (M+H)⁺.

EXAMPLE 17(210)2-(2-((2R)-2-(4-fluoro-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.41 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(211)2-(2-((2R)-2-(4-cyanomethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.21 minutes;

MASS data (ESI, Pos. 20 V): 417 (M+H)⁺.

EXAMPLE 17(212)2-(2-((2R)-2-(3-hydroxymethyl-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.05 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(213)2-(2-((2R)-2-(5-methoxy-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.37 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(214)2-(2-((2R)-2-(2-methoxy-6-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.00 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(215)2-(2-((2R)-2-(2-cyanomethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.33 minutes;

MASS data (ESI, Pos. 20 V): 417 (M+H)⁺.

EXAMPLE 17(216)2-(2-((2R)-5-oxo-2-(5,6,7,8-tetrahydronaphthalen-1-ylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.58 minutes;

MASS data (ESI, Pos. 20 V): 432 (M+H)⁺.

EXAMPLE 17(217)2-(2-((2R)-2-(indan-5-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.23 minutes;

MASS data (ESI, Pos. 20 V): 418 (M+H)⁺.

EXAMPLE 17(218)2-(2-((2R)-2-(1,3-benzodioxol-5-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.07 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(219)2-(2-((2R)-5-oxo-2-(quinolin-5-ylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.91 minutes;

MASS data (ESI, Pos. 20 V): 429 (M+H)⁺.

EXAMPLE 17(220)2-(2-((2R)-5-oxo-2-(quinolin-6-ylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.89 minutes;

MASS data (ESI, Pos. 20 V): 429 (M+H)⁺.

EXAMPLE 17(221)2-(2-((2R)-5-oxo-2-(quinolin-8-ylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.08 minutes;

MASS data (ESI, Pos. 20 V): 429 (M+H)⁺.

EXAMPLE 17(222)2-(2-((2R)-2-(2-cyanophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.31 minutes;

MASS data (ESI, Pos. 20 V): 403 (M+H)⁺.

EXAMPLE 17(223)2-(2-((2R)-2-(2-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.37 minutes;

MASS data (ESI, Pos. 20 V): 396 (M+H)⁺.

EXAMPLE 17(224)2-(2-((2R)-2-(2,4-difluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.41 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(225)2-(2-((2R)-5-oxo-2-(2,4,5-trifluorophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.44 minutes;

MASS data (ESI, Pos. 20 V): 432 (M+H)⁺.

EXAMPLE 17(226)2-(2-((2R)-5-oxo-2-(2,4,6-trifluorophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.43 minutes;

MASS data (ESI, Pos. 20 V): 432 (M+H)⁺.

EXAMPLE 17(227)2-(2-((2R)-2-(2,5-difluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.41 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(228)2-(2-((2R)-2-(2,6-difluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.38 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(229)2-(2-((2R)-2-(2-chlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.46 minutes;

MASS data (ESI, Pos. 20 V): 412 (M+H)⁺.

EXAMPLE 17(230)2-(2-((2R)-2-(2-ethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.28 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(231)2-(2-((2R)-2-(2-methylthiophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.50 minutes;

MASS data (ESI, Pos. 20 V): 424 (M+H)⁺.

EXAMPLE 17(232)2-(2-((2R)-2-(2-isopropylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.55 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(233)2-(2-((2R)-2-(2,4,6-trimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.15 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(234)2-(2-((2R)-2-(2-isopropyl-6-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.35 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(235)2-(2-((2R)-2-(2-ethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.48 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(236)2-(2-((2R)-2-(2-ethyl-6-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.27 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(237)2-(2-((2R)-2-(2,6-diethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.40 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(238)2-(2-((2R)-2-(3-cyanophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.31 minutes;

MASS data (ESI, Pos. 20 V): 403 (M+H)⁺.

EXAMPLE 17(239)2-(2-((2R)-2-(3-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.38 minutes;

MASS data (ESI, Pos. 20 V): 396 (M+H)⁺.

EXAMPLE 17(240)2-(2-((2R)-2-(3,4-difluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.43 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(241)2-(2-((2R)-2-(5-fluoro-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.48 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(242)2-(2-((2R)-2-(3-chlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.48 minutes;

MASS data (ESI, Pos. 20 V): 412 (M+H)⁺.

EXAMPLE 17(243)2-(2-((2R)-2-(3-chloro-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.57 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(244)2-(2-((2R)-2-(3-chloro-4-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.50 minutes;

MASS data (ESI, Pos. 20 V): 430 (M+H)⁺.

EXAMPLE 17(245)2-(2-((2R)-2-(3-chloro-4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(246)2-(2-((2R)-2-(3,5-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.32 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(247)2-(2-((2R)-2-(2-methoxy-5-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.25 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(248)2-(2-((2R)-2-(3-ethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.38 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(249)2-(2-((2R)-2-(4-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.26 minutes;

MASS data (ESI, Pos. 20 V): 396 (M+H)⁺.

EXAMPLE 17(250)2-(2-((2R)-2-(4-chloro-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.57 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(251)2-(2-((2R)-2-(4-nitrophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.29 minutes;

MASS data (ESI, Pos. 20 V): 423 (M+H)⁺.

EXAMPLE 17(252)2-(2-((2R)-2-(4-ethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.09 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(253)2-(2-((2R)-2-(4-ethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.31 minutes;

MASS data (ESI, Pos. 20 V): 406 (M+H)⁺.

EXAMPLE 17(254)2-(2-((2R)-2-(4-(2-hydroxyethyl)phenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.95 minutes;

MASS data (ESI, Pos. 20 V): 422 (M+H)⁺.

EXAMPLE 17(255)2-(2-((2R)-5-oxo-2-(4-propylphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.44 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(256)2-(2-((2R)-2-(4-butylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(257)2-(2-((2R)-5-oxo-2-(2-propylphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.61 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(258)2-(2-((2R)-2-(4-(1-methylpropyl)phenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.53 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(259)2-(2-((2R)-2-(4-chloro-2-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.52 minutes;

MASS data (ESI, Pos. 20 V): 430 (M+H)⁺.

EXAMPLE 17(260)2-(2-((2R)-5-oxo-2-(2,3,4-trifluorophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.48 minutes;

MASS data (ESI, Pos. 20 V): 432 (M+H)⁺.

EXAMPLE 17(261)2-(2-((2R)-2-(2-butylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.72 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(262)2-(2-((2R)-2-(2-chloro-4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.57 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(263)2-(2-((2R)-2-(2-isopropenylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 418 (M+H)⁺.

EXAMPLE 17(264)2-(2-((2R)-2-(3-fluoro-4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.46 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(265)2-(2-((2R)-2-(3-methylthiophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.43 minutes;

MASS data (ESI, Pos. 20 V): 424 (M+H)⁺.

EXAMPLE 17(266)2-(2-((2R)-2-(2-(1-methylpropyl)phenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.66 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(267)2-(2-((2R)-2-(3-fluoro-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.47 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(268)2-(2-((2R)-2-(2-fluoro-4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.47 minutes;

MASS data (ESI, Pos. 20 V): 410 (M+H)⁺.

EXAMPLE 17(269)2-(2-((2R)-2-(1H-indazol-6-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 418 (M+H)⁺.

EXAMPLE 17(270)2-(2-((2R)-2-(1,4-benzodioxan-6-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.05 minutes;

MASS data (ESI, Pos. 20 V): 436 (M+H)⁺.

EXAMPLE 17(271)2-(2-((2R)-2-(4-methyl-2-oxo-2H-chromen-7-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.22 minutes;

MASS data (ESI, Pos. 20 V): 460 (M+H)⁺.

EXAMPLE 17(272)2-(2-((2R)-2-(2-bromophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.49 minutes;

MASS data (ESI, Pos. 20 V): 458 (M+H)⁺.

EXAMPLE 17(273)2-(2-((2R)-2-(2-bromo-4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 472 (M+H)⁺.

EXAMPLE 17(274)2-(2-((2R)-2-(2,3-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.54 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(275)2-(2-((2R)-2-(2,4-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.59 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(276)2-(2-((2R)-2-(2,5-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(277)2-(2-((2R)-2-(2-chloro-5-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.63 minutes;

MASS data (ESI, Pos. 20 V): 480 (M+H)⁺.

EXAMPLE 17(278)2-(2-((2R)-5-oxo-2-(2-trifluoromethylphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.51 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(279)2-(2-((2R)-2-(3-bromophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.47 minutes;

MASS data (ESI, Pos. 20 V): 458 (M+H)⁺.

EXAMPLE 17(280)2-(2-((2R)-2-(3,4-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.58 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(281)2-(2-((2R)-2-(3,5-dichlorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.63 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(282)2-(2-((2R)-2-(5-chloro-2-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.47 minutes;

MASS data (ESI, Pos. 20 V): 442 (M+H)⁺.

EXAMPLE 17(283)2-(2-((2R)-5-oxo-2-(3-trifluoromethylphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.54 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(284)2-(2-((2R)-2-(4-cyanophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.23 minutes;

MASS data (ESI, Pos. 20 V): 403 (M+H)⁺.

EXAMPLE 17(285)2-(2-((2R)-2-(4-bromophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.48 minutes;

MASS data (ESI, Pos. 20 V): 458 (M+H)⁺.

EXAMPLE 17(286)2-(2-((2R)-2-(4-bromo-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.58 minutes;

MASS data (ESI, Pos. 20 V): 472 (M+H)⁺.

EXAMPLE 17(287)2-(2-((2R)-2-(4-bromo-3-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 472 (M+H)⁺.

EXAMPLE 17(288)2-(2-((2R)-2-(4-fluoro-3-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 464 (M+H)⁺.

EXAMPLE 17(289)2-(2-((2R)-2-(4-chloro-3-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.64 minutes;

MASS data (ESI, Pos. 20 V): 480 (M+H)⁺.

EXAMPLE 17(290)2-(2-((2R)-2-(4-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.96 minutes;

MASS data (ESI, Pos. 20 V): 408 (M+H)⁺.

EXAMPLE 17(291)2-(2-((2R)-2-(4-butoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.29 minutes;

MASS data (ESI, Pos. 20 V): 450 (M+H)⁺.

EXAMPLE 17(292)2-(2-((2R)-5-oxo-2-(4-pentylphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.66 minutes;

MASS data (ESI, Pos. 20 V): 448 (M+H)⁺.

EXAMPLE 17(293)2-(2-((2R)-2-(4-hexylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.79 minutes;

MASS data (ESI, Pos. 20 V): 462 (M+H)⁺.

EXAMPLE 17(294)2-(2-((2R)-2-(4-heptylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.92 minutes;

MASS data (ESI, Pos. 20 V): 476 (M+H)⁺.

EXAMPLE 17(295)2-(2-((2R)-2-(3-aminocarbonylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 421 (M+H)⁺.

EXAMPLE 17(296)2-(2-((2R)-2-(2,5-dimethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.25 minutes;

MASS data (ESI, Pos. 20 V): 438 (M+H)⁺.

EXAMPLE 17(297)2-(2-((2R)-5-oxo-2-(3,4,5-trimethoxyphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.11 minutes;

MASS data (ESI, Pos. 20 V): 468 (M+H)⁺.

EXAMPLE 17(298)2-(2-((2R)-2-(2,6-diisopropylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.55 minutes;

MASS data (ESI, Pos. 20 V): 462 (M+H)⁺.

EXAMPLE 17(299)2-(2-((2R)-2-(4-bromo-2-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.52 minutes;

MASS data (ESI, Pos. 20 V): 476 (M+H)⁺.

EXAMPLE 17(300)2-(2-((2R)-2-(2-chloro-5-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.44 minutes;

MASS data (ESI, Pos. 20 V): 442 (M+H)⁺.

EXAMPLE 17(301)2-(2-((2R)-2-(2,5-diethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.46 minutes;

MASS data (ESI, Pos. 20 V): 466 (M+H)⁺.

EXAMPLE 17(302)2-(2-((2R)-2-(2-methylquinolin-8-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.98 minutes;

MASS data (ESI, Pos. 20 V): 443 (M+H)⁺.

EXAMPLE 17(303)2-(2-((2R)-2-(2-(1-methylpropyl)-6-ethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.59 minutes;

MASS data (ESI, Pos. 20 V): 462 (M+H)⁺.

EXAMPLE 17(304)2-(2-((2R)-2-(5-chloro-2,4-dimethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.26 minutes;

MASS data (ESI, Pos. 20 V): 472 (M+H)⁺.

EXAMPLE 17(305)2-(2-((2R)-2-(5-chloro-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.54 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(306)2-(2-((2R)-2-(1H-indazol-5-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.85 minutes;

MASS data (ESI, Pos. 20 V): 418 (M+H)⁺.

EXAMPLE 17(307)2-(2-((2R)-5-oxo-2-(4-trifluoromethoxyphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.59 minutes;

MASS data (ESI, Pos. 20 V): 462 (M+H)⁺.

EXAMPLE 17(308)2-(2-((2R)-2-(4-cyano-3-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.42 minutes;

MASS data (ESI, Pos. 20 V): 471 (M+H)⁺.

EXAMPLE 17(309)2-(2-((2R)-2-(2-bromo-4-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.51 minutes;

MASS data (ESI, Pos. 20 V): 476 (M+H)⁺.

EXAMPLE 17(310)2-(2-((2R)-2-(2-chloro-4-fluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.47 minutes;

MASS data (ESI, Pos. 20 V): 430 (M+H)⁺.

EXAMPLE 17(311)2-(2-((2R)-5-oxo-2-(2,3,4-trichlorophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.68 minutes;

MASS data (ESI, Pos. 20 V): 482 (M+H)⁺.

EXAMPLE 17(312)2-(2-((2R)-2-(5-isopropyl-2-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.62 minutes;

MASS data (ESI, Pos. 20 V): 434 (M+H)⁺.

EXAMPLE 17(313)2-(2-((2R)-2-(2-methylquinolin-6-ylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.91 minutes;

MASS data (ESI, Pos. 20 V): 443 (M+H)⁺.

EXAMPLE 17(314)2-(2-((2R)-2-(3-isopropoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.41 minutes;

MASS data (ESI, Pos. 20 V): 436 (M+H)⁺.

EXAMPLE 17(315)2-(2-((2R)-5-oxo-2-(4-trifluoromethylphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.55 minutes;

MASS data (ESI, Pos. 20 V): 446 (M+H)⁺.

EXAMPLE 17(316)2-(2-((2R)2-(3-methylaminocarbonylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.01 minutes;

MASS data (ESI, Pos. 20 V): 435 (M+H)⁺.

EXAMPLE 17(317)2-(2-((2R)-2-(3-chloro-2,6-diethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.81 minutes;

MASS data (ESI, Pos. 20 V): 468 (M+H)⁺.

EXAMPLE 17(318)2-(2-((2R)-2-(3-isopropylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.46 minutes;

MASS data (ESI, Pos. 20 V): 420 (M+H)⁺.

EXAMPLE 17(319)2-(2-((2R)-2-(2,3-dimethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.26 minutes;

MASS data (ESI, Pos. 20 V): 438 (M+H)⁺.

EXAMPLE 17(320)2-(2-((2R)-2-(3-methoxy-5-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 476 (M+H)⁺.

EXAMPLE 17(321)2-(2-((2R)-2-(4-(morpholin-4-yl)phenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 2.87 minutes;

MASS data (ESI, Pos. 20 V): 463 (M+H)⁺.

EXAMPLE 17(322)2-(2-((2R)-2-(2-fluoro-5-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 464 (M+H)⁺.

EXAMPLE 17(323)2-(2-((2R)-2-(2-chloro-5-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.54 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(324)2-(2-((2R)-5-oxo-2-(3,4,5-trichlorophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.71 minutes;

MASS data (ESI, Pos. 20 V): 482 (M+H)⁺.

EXAMPLE 17(325)2-(2-((2R)-2-(3-chloro-4-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.30 minutes;

MASS data (ESI, Pos. 20 V): 442 (M+H)⁺.

EXAMPLE 17(326)2-(2-((2R)-2-(4-chloro-2-methoxy-5-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.55 minutes;

MASS data (ESI, Pos. 20 V): 456 (M+H)⁺.

EXAMPLE 17(327)2-(2-((2R)-5-oxo-2-(4-pentyloxyphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.40 minutes;

MASS data (ESI, Pos. 20 V): 464 (M+H)⁺.

EXAMPLE 17(328)2-(2-((2R)-2-(4-hexyloxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.52 minutes;

MASS data (ESI, Pos. 20 V): 478 (M+H)⁺.

EXAMPLE 17(329)2-(2-((2R)-2-(2,3-difluorophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.40 minutes;

MASS data (ESI, Pos. 20 V): 414 (M+H)⁺.

EXAMPLE 17(330)2-(2-((2R)-5-oxo-2-(2,3,4,5-tetrafluorophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.50 minutes;

MASS data (ESI, Pos. 20 V): 450 (M+H)⁺.

EXAMPLE 17(331)2-(2-((2R)-2-(5-t-butyl-2-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.49 minutes;

MASS data (ESI, Pos. 20 V): 464 (M+H)⁺.

EXAMPLE 17(332)2-(2-((2R)-2-(3-chloro-4-cyanophenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.35 minutes;

MASS data (ESI, Pos. 20 V): 437 (M+H)⁺.

EXAMPLE 17(333)2-(2-((2R)-5-oxo-2-(2-trifluoromethoxyphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.57 minutes;

MASS data (ESI, Pos. 20 V): 462 (M+H)⁺.

EXAMPLE 17(334)2-(2-((2R)-5-oxo-2-(4-trifluoromethylthiophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.70 minutes;

MASS data (ESI, Pos. 20 V): 478 (M+H)⁺.

EXAMPLE 17(335)2-(2-((2R)-5-oxo-2-(3-trifluoromethoxyphenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.59 minutes;

MASS data (ESI, Pos. 20 V): 462 (M+H)⁺.

EXAMPLE 17(336)2-(2-((2R)-2-(2-methoxy-5-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 476 (M+H)⁺.

EXAMPLE 17(337)2-(2-((2R)-2-(2-chloro-4,6-dimethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 440 (M+H)⁺.

EXAMPLE 17(338)2-(2-((2R)-2-(2-chloro-4-fluoro-5-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.58 minutes;

MASS data (ESI, Pos. 20 V): 444 (M+H)⁺.

EXAMPLE 17(339)2-(2-((2R)-2-(2-cyano-4,5-dimethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.20 minutes;

MASS data (ESI, Pos. 20 V): 463 (M+H)⁺.

EXAMPLE 17(340)2-(2-((2R)-2-(2-fluoro-3-trifluoromethylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.57 minutes;

MASS data (ESI, Pos. 20 V): 464 (M+H)⁺.

EXAMPLE 17(341)2-(2-((2R)-2-(3-fluoro-4-methoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.23 minutes;

MASS data (ESI, Pos. 20 V): 426 (M+H)⁺.

EXAMPLE 17(342)2-(2-((2R)-2-(4-difluoromethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.39 minutes;

MASS data (ESI, Pos. 20 V): 444 (M+H)⁺.

EXAMPLE 17(343)2-(2-((2R)-2-(3-bromo-4-methylphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.56 minutes;

MASS data (ESI, Pos. 20 V): 472 (M+H)⁺.

EXAMPLE 17(344)2-(2-((2R)-2-(2-difluoromethoxyphenylaminomethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.44 minutes;

MASS data (ESI, Pos. 20 V): 444 (M+H)⁺.

EXAMPLE 17(345)2-(2-((2R)-5-oxo-2-(3-trifluoromethylthiophenylaminomethyl)pyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

HPLC retention time: 3.66 minutes;

MASS data (ESI, Pos. 20 V): 478 (M+H)⁺.

REFERENCE EXAMPLE 21 t-butyl(1R)-2-benzyloxy-1-hydroxymethylethylcarbamate

Under an atmosphere of argon, to a solution of 2,5-dioxopyrrolidin-1-ylO-benzyl-N-t-butoxycarbonyl-L-serinate (4.41 g) in tetrahydrofuran(30mL) was added sodium borohydride (644 mg) in ice bath and the mixturewas stirred at room temperature overnight. Water was added to thereaction solution, which was extracted with ethyl acetate. The organiclayer was washed with an aqueous saturated ammonium chloride solutionand brine, dried over anhydrous magnesium sulfate and concentrated togive the title compound (3.30 g) having the following physical data.

TLC: Rf 0.42 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.45 (s, 9 H) 2.61 (br. s., 1 H) 3.72 (m, 5 H) 4.53 (s, 2H) 5.17 (br. s., 1 H) 7.34 (m, 5 H).

REFERENCE EXAMPLE 22 (2R)-2-amino-3-benzyloxypropanol hydrochloride

To a solution of the compound prepared in Reference Example 21 (3.30 g)in toluene (20 mL) was added 4N hydrogen chloride dioxane solution (4mL) and the mixture was stirred at room temperature for 2 hours and at60° C. for 1 hour. After cooling, hexane was added to the reactionmixture, which was filtrated. The obtained residue was dried to give thetitle compound (2.18 g) having the following physical data.

TLC: Rf 0.21 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 2.31 (br. s., 4 H) 3.69 (m, 5 H) 4.55 (s, 2 H) 7.31 (m, 5H).

REFERENCE EXAMPLE 23 (4R)-4-benzyloxymethyl-2-oxo-1,3-oxazolidine

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 22 (2.15 g) in tetrahydrofuran (20 mL) were1,1′-carbonyldiimidazole (1.77 g) and triethylamine (2.75 mL) in icebath and the mixture was stirred at room temperature overnight. To thereaction solution was added 1,1′-carbonyldiimidazole (1.77 g) and themixture was stirred at 60° C. for 3 hours. After cooling, hydrochloricacid was added to the reaction solution. The reaction mixture wasextracted with ethyl acetate. The obtained organic layer was washed withwater and brine, dried over anhydrous magnesium sulfate and concentratedto give the title compound (2.00 g) having the following physical data.

TLC: Rf 0.68 (ethyl acetate);

NMR (CDCl₃): δ 3.47 (d, J=6.20 Hz, 2 H) 4.03 (m, 1 H) 4.11 (dd, J=8.40,5.10 Hz, 1 H) 4.45 (t, J=8.40 Hz, 1 H) 4.54 (s, 2 H) 5.62 (br. s., 1 H)7.32 (m, 5 H).

REFERENCE EXAMPLE 24(4R)-4-benzyloxymethyl-2-oxo-1,3-oxazolidin-1-ylacetic acid ethyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 23 (2.00 g) and bromoethyl acetate (2.42 g) intetrahydrofuran(20 mL) was added potassium t-butoxide (1.29 g) and themixture was stirred at room temperature overnight. Water was added tothe reaction solution, which was extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated. The obtained residue was purified bycolumn chromatography on silica gel (n-hexane:ethyl acetate=1:1) to givethe title compound (1.18 g) having the following physical data.

TLC: Rf 0.42 (n-hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.24 (t, J=7.10 Hz, 3 H) 3.52 (dd, J=9.60, 4.00 Hz, 1 H)3.60 (dd, J=9.60, 6.60 Hz, 1 H) 3.97 (d, J=18.00 Hz, 1 H) 4.01 (dd,J=8.70, 6.30 Hz, 1 H) 4.15 (m, 3 H) 4.22 (d, J=18.00 Hz, 1 H) 4.44 (t,J=8:70 Hz, 1 H) 4.47 (d, J=12.00 Hz, 1 H) 4.53 (d, J=12.00 Hz, 1 H) 7.33(m, 5 H).

REFERENCE EXAMPLE 25(4R)-4-hydroxymethyl-2-oxo-1,3-oxazolidin-1-ylacetic acid ethyl ester

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 24 (1.17 g) in ethanol (20 mL) was added palladiumhydroxide on carbon (200 mg). Under an atmosphere of hydrogen, themixture was stirred overnight. The reaction mixture was filtrated andconcentrated to give the title compound (810 mg) having the followingphysical data.

TLC: Rf 0.42 (ethyl acetate);

NMR (CDCl₃): δ 1.32 (t, J=7.10 Hz, 3 H) 3.63 (m, 3 H) 3.74 (d, J=18.00Hz, 1 H) 3.86 (m,1 H) 4.26 (m, 2 H) 4.39 (d, J=18.00 Hz, 1 H) 4.42 (d,J=8.00 Hz, 1 H)

REFERENCE EXAMPLE 26(4R)-4-(3,5-dichlorophenoxymethyl)-2-oxo-1,3-oxazalidin-1-ylacetic acidethyl ester

Under an atmosphere of argon, diethyl azodicarboxylate (40% solution intoluene) (0.54 mL)was added dropwise to a solution of the compoundprepared in Reference Example 25 (203 mg), 3,5-dichlorophenol (196 mg)and triphenylphosphine (314 mg) in tetrahydrofuran (5 mL) and themixture was stirred at room temperature for 4 hours. Triphenylphosphine(157 mg) and diethyl azodicarboxylate (40% solution in toluene) (0.27mL) was added to the reaction solution, which was stirred at roomtemperature for 4 hours. The reaction solution was concentrated and theobtained residue was purified by column chromatography on silica gel(methylene chloride:ethyl acetate=100:3) to give the title compound (271mg) having the following physical data.

TLC: Rf 0.45 (methylene chloride:ethyl acetate=4:1);

NMR (CDCl₃): δ 1.26 (t, J=7.14 Hz, 3 H) 4.14 (m, 7 H) 4.37 (m, 1 H) 4.57(t, J=8.93 Hz, 1 H) 6.78 (d, J=1.65 Hz, 2 H) 7.02 (t, J=1.65 Hz, 1 H).

EXAMPLE 18(4R)-4-(3,5-dichlorophenoxymethyl)-1-(2-hydroxyethyl)-2-oxo-1,3-oxazolidine

Under an atmosphere of argon, to a solution of the compound prepared inReference Example 26 (270 mg) in tetrahydrofuran (5 mL) was added sodiumborohydride (88 mg) and the mixture was stirred at room temperatureovernight. Water was added to the reaction mixture, which was extractedwith ethyl acetate. The organic layer was washed with water and brine,dried over anhydrous magnesium sulfate and concentrated. The obtainedresidue was purified by column chromatography on silica gel (ethylacetate) to give the title compound (138 mg) having the followingphysical data.

TLC: Rf 0.21 (methylene chloride:ethyl acetate=1:1);

NMR (CDCl₃): δ 3.41 (m, 1 H) 3.59 (m, 1 H) 3.86 (m, 2 H) 4.10 (m, 2 H)4.28 (m, 2 H) 4.51 (t, J=8.10 Hz, 1 H) 6.82 (d, J=1.80 Hz, 2 H) 7.02 (t,J=1.80 Hz, 1 H).

REFERENCE EXAMPLE 27(2-((4R)-4-(3,5-dichlorophenoxymethyl)-2-oxo-1,3-oxazolidin-1-yl)ethylmethanesulfonate

methanesulfonyl chloride (0.051 mL) was added dropwise to the compoundprepared in Example 18 (135 mg) and triethylamine (0.12 mL) in methylenechloride (2 mL) in ice bath and the mixture was stirred for 1 hour.Hydrochloric acid was added to the reaction solution, which wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous magnesium sulfate and concentrated togive the title compound (193 mg) having the following physical data.

TLC: Rf 0.53 (methylene chloride:ethyl acetate=1:1);

NMR (CDCl₃): δ 3.03 (s, 3 H) 3.58 (m, 1 H) 3.81 (m, 1 H) 4.09 (m, 2 H)4.23 (dd, J=8.50, 4.80 Hz, 1 H) 4.38 (m, 3 H) 4.53 (t, J=8.50 Hz, 1 H)6.83 (d, J=1.80 Hz, 2 H) 7.03 (t, J=1.80 Hz, 1 H).

REFERENCE EXAMPLE 28S-((4R)-4-(3,5-dichlorophenoxymethyl)-2-oxo-1,3-oxazolidin-1-yl)ethylethanethioate

Under an atmosphere of argon, a solution of the compound prepared inReference Example 27 (193 mg) and potassium thioacetate (75 mg) indimethylformamide (2 mL) was stirred at 60° C. for 2 hours. Water wasadded to the reaction solution, which was extracted with ethyl acetate.The organic layer was washed with water and brine, dried over anhydrousmagnesium sulfate and concentrated to give the title compound (165 mg)having the following physical data.

TLC: Rf 0.65 (methylene chloride:ethyl acetate=1:2);

NMR (CDCl₃): δ 2.34 (s, 3 H) 3.07 (m, 2 H) 3.37 (m, 1 H) 3.60 (m, 1 H)4.17 (m, 4 H) 4.46 (m, 1 H) 6.85 (d, J=1.80 Hz, 2 H) 7.02 (t, J=1.80 Hz,1 H).

EXAMPLE 192-(2-((4S)-4-(3,5-dichlorophenoxymethyl)-2-oxo-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylicacid ethyl ester

Under an atmosphere of argon, a solution of the compound preparedReference Example 28 (165 mg) and ethyl 2-bromothiazole-4-carboxylate(114 mg) in ethanol was deaerated and potassium carbonate (91 mg) wasadded thereto. The mixture was stirred at room temperature overnight.Water was added to the reaction solution, which was extracted with ethylacetate. The organic layer was washed with water and brine, dried overanhydrous magnesium sulfate and concentrated. The obtained residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=1:1) to give the compound of the present invention (144 mg)having the following physical data.

TLC: Rf 0.43 (toluene:ethyl acetate=1:1);

NMR (CDCl₃): δ 1.39 (t, J=7.10 Hz, 3 H) 3.33 (ddd, J=13.80, 9.30, 6.00Hz, 1 H) 3.49 (ddd, J=13.80, 9.30, 5.10 Hz, 1 H) 3.65 (ddd, J=14.30,9.30, 5.10 Hz, 1 H) 3.81 (ddd, J=14.30, 9.30, 6.00 Hz, 1 H) 4.07 (dd,J=10.50, 3.00 Hz, 1 H) 4.40 (m, 5 H) 4.69 (dd, J=10.50, 3.00 Hz, 1 H)6.90 (d, J=1.80 Hz, 2 H) 6.96 (t, J=1.80 Hz, 1 H) 8.00 (s, 1 H).

EXAMPLES 20(1) AND 20(2)

By the same procedure as described in Example 2, using the compoundprepared in Example 19 or a corresponding ester instead of the compoundprepared in Example 1, the following compounds of the present inventionwere obtained.

EXAMPLE 20(1)2-(2-((4S)-4-(3,5-dichlorophenoxymethyl)-2-oxo-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.58 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 3.37 (ddd, J=13.50, 9.30, 6.00 Hz, 1 H) 3.53 (ddd,J=13.50, 9.30, 6.00 Hz, 1 H) 3.69 (ddd, J=14.10, 9.30, 5.20 Hz, 1 H)3.83 (ddd, J=14.10, 9.30, 6.00 Hz, 1 H) 4.06 (m, 1 H) 4.36 (m, 4 H) 6.84(d, J=1.80 Hz, 2 H) 6.98 (t, J=1.80 Hz, 1 H) 8.14 (s, 1 H).

EXAMPLE 20(2)2-(2-((4S)-2-oxo-4-((3-(trifluoromethoxy)phenoxy)methyl)-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.26 (chloroform:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 3.39 (m, J=14.20, 9.00, 5.90 Hz, 1 H) 3.54 (ddd, J=14.20,9.00, 5.30 Hz, 1 H) 3.71 (ddd, J=14.20, 9.00, 5.30 Hz, 1 H) 3.85 (ddd,J=14.20, 9.00, 5.90 Hz, 1 H) 4.08 (m, 1 H) 4.31 (m, 3 H) 4.47 (t, J=7.90Hz, 1 H) 6.78 (s, 1 H) 6.86 (m, 2 H) 7.31 (d, J=8.10 Hz, 1 H) 8.13 (s, 1H).

EXAMPLE 212-(2-((2R)-2-(3,5-dichlorophenoxymethyl)-5-thioxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid ethyl ester

To a solution of the compound prepared in Example 5(32) (190 mg) intoluene (3 mL) was added Lawesson's Reagent (97 mg) and the mixture wasstirred at 50° C. for 1 hour. After cooling to room temperature, thereaction solution was purified by column chromatography on silica gel(hexane:ethyl acetate=4:1) to give the compound of the present inventionhaving the following physical data.

TLC: Rf 0.35 (hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 1.34 (t, J=7.14 Hz, 3 H) 2.17 (m, 2 H) 2.97 (m, 1 H) 3.21(m, 2 H) 3.64 (m, 1 H) 4.03 (m, 2 H) 4.19 (m, 1 H) 4.36 (m, 3 H) 4.92(dd, J=10.71, 2.75 Hz, 1 H) 6.86 (m, 3 H) 7.94 (s, 1 H).

EXAMPLE 21(1) AND 21(2)

By the same procedure as described in Example 21, using a correspondingester instead of the compound prepared in Example 5(32), the followingcompounds of the present invention were obtained.

EXAMPLE 21(1)2-(2-((4S)-4-(3,5-dichlorophenoxymethyl)-2-thioxo-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazol-4-carboxylicacid methyl ester

TLC: Rf 0.47 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 3.36 (ddd, J=13.50, 9.90, 5.10 Hz, 1 H) 3.65 (ddd,J=13.50, 10.20, 5.10 Hz, 1 H) 3.93 (s, 3 H) 3.97 (m, 1 H) 4.14 (m, 2 H)4.63 (m, 3 H) 4.92 (m, 1 H) 6.93 (d, J=1.80 Hz, 2 H) 6.97 (t, J=1.80 Hz,1 H) 8.02 (s, 1 H).

EXAMPLE 21(2)2-(2-((4S)-2-thioxo-4-(3-trifluoromethoxyphenoxymethyl)-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazol-4-carboxylicacid methyl ester

TLC: Rf 0.43 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 3.41 (ddd, J=13.70, 9.70, 5.30 Hz, 1 H) 3.65 (ddd,J=13.70, 9.80, 5.40 Hz, 1 H) 3.89 (s, 3 H) 3.96 (ddd, J=13.80, 9.60,5.50 Hz, 1 H) 4.17 (m, 2 H) 4.64 (m, 3 H) 4.82 (m, 1 H) 6.86 (m, 3 H)7.26 (m, 1 H) 8.01 (s, 1 H).

EXAMPLES 22(1) TO 22(3)

By the same procedure as described in Example 2, using the compoundprepared in 21, 21(1) or 21(2) instead of the compound prepared inExample 1, the following compounds of the present invention wereobtained.

EXAMPLE 22(1)2-(2-((2R)-2-(3,5-dichlorophenoxymethyl)-5-thioxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.26 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.17 (s, 1H), 6.96 (t, J=2.1 Hz, 1H), 6.86 (d, J=2.1 Hz,2H), 4.66 (dd, J=10.2, 3.0 Hz, 1H), 4.44-4.24 (m, 2H), 4.16-3.95 (m,2H), 3.73 (m, 1H), 3.39 (m, 1H), 3.17 (m, 1H), 3.04 (m, 1H), 2.2 6 (m,1H), 2.06 (m, 1H).

EXAMPLE 22(2)2-(2-((4S)-4-(3,5-dichlorophenoxymethyl)-2-thioxo-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.57 (methylene chloride:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 3.43 (m, 1 H) 3.70 (m, 1 H) 3.96 (m, 1 H) 4.08 (m, 1 H)4.19 (m, 1 H) 4.57 (m, 4 H) 6.87 (d, J=1.80 Hz, 2 H) 6.98 (t, J=1.80 Hz,1 H) 8.16 (s, 1 H).

EXAMPLE 22(3)2-(2-((4S)-2-thioxo-4-(3-trifluoromethoxyphenoxymethyl)-1,3-oxazolidin-3-yl)ethylthio)-1,3-thiazole-4-carboxylicacid

TLC: Rf 0.54 (methylene chloride:methanol:acetic acid=90:10:1);

NMR (CDCl₃): δ 3.46 (m, 1 H) 3.70 (m, 1 H) 3.97 (m, 1 H) 4.10 (m, 1 H)4.22 (m, 1 H) 4.58 (m, 4 H) 6.84 (m, 3 H) 7.28 (t, J=8.20 Hz, 1H) 8.16(s, 1 H).

FORMULATION EXAMPLE 1

The following components were admixed in a conventional method, punchedout to give 100 tablets each containing 0.5 mg of active ingredient.

2-(2-(2-(4-n-butylphenyl)-5-oxopyrrolidin-1-  250 mg (content 50 mg)yl)ethylthio)thiazole-4- carboxylic acid α-cyclodextrin calciumcarboxymethylcellulose  200 mg magnesium stearate  100 mgmicrocrystalline cellulose  9.2 g

FORMULATION EXAMPLE 2

After mixing the following components by a conventional method, theresulting solution was sterilized by a conventional method and 1 mlportions thereof were filled in vials, respectively, and freeze-dried bya conventional method to obtain 100 vials of injection containing each0.2 mg of the active ingredient.

2-(2-(2-(4-n-butylphenyl)-5-oxopyrrolidin-1- 100 mg (content 20 mg)yl)ethylthio)thiazole-4-carboxylic acid α-cyclodextrin Mannitol  5 gDistilled water 100 ml

1. An 8-azaprostaglandin derivative compound represented by formula(I-a1-1)

(wherein Y^(a) is —S— or —SO₂—; ring6 is 5 or 6 memberedmono-heterocyclic aryl consisting of hetero atoms selected from 1 to 4nitrogen, 1 to 2 oxygen, and/or 1 to 2 sulfur atoms which may bepartially or fully saturated; R¹⁰⁰ is a hydrogen atom or C1-4 alkyl;U^(3a-1) is ring4; ring 4 is C3-15 mono-, bi- or tri-carbocyclic arylwhich may be partially or fully saturated; ring4 may be substituted by 1to 5 R; R is (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4)C1-10 alkoxy, (5) C1-10 alkylthio, (6) halogen, (7) hydroxy, (8) nitro,(9) —NR¹⁵R¹⁶, (10) C1-10 alkyl substituted by C1-10 alkoxy, (11) C1-10alkyl substituted by 1 to 3 halogen atom(s), (12) C1-C10 alkylsubstituted by C1-10 alkoxy substituted by 1 to 3 halogen atom(s), (13)C1-10 alkyl substituted by —NR¹⁵R¹⁶, (14) ring5, (15) —O-ring5, (16)C1-10 alkyl substituted by ring5, (17) C2-10 alkenyl substituted byring5, (18) C2-10 alkynyl substituted by ring5, (19) C1-10 alkoxysubstituted by ring5, (20) C1-10 alkyl substituted by —O-ring5, (21)COOR¹⁷, (22) C1-10 alkoxy substituted by 1 to 4 halogen atom(s), (23)formyl, (24) C1-10 alkyl substituted by hydroxy or (25) C2-10 acyl; R¹⁵,R¹⁶ and R¹⁷ are, each independently, (1) a hydrogen atom or (2) C1-10alkyl; ring5 is (1) C3-15 mono-, bi- or tri-carbocyclic aryl which maybe partially or fully saturated or (2) 3- to 15-membered mono-, bi- ortri-heterocyclic aryl which may be partially or fully saturated andcontains a hetero atom(s) selected from 1 to 4 nitrogen, 1 to 2 oxygenand/or 1 to 2 sulfur atom(s); ring5 may be substituted by 1 to 3sustituent(s) selected from following (1)-(9): (1) C1-10 alkyl, (2)C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10 alkoxy, (5) C1-10 alkylsubstituted by C1-10 alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10alkyl substituted by 1 to 3 halogen atom(s), (9) C1-10 alkyl substitutedby C1-10 alkoxy substituted by 1 to 3 halogen atom(s); apharmaceutically acceptable salt thereof or a cyclodextrin clathratethereof.
 2. A pharmaceutical composition, which comprises, the8-azaprostaglandin derivative compound according to claim 1, apharmaceutically acceptable salt thereof or a cyclodextrin clathratethereof and a pharmaceutically acceptable carrier.
 3. The pharmaceuticalcomposition according to claim 2, which is EP₂ or EP₄ receptor agonist.4. The 8-azaprostaglandin derivative compound according to claim 1,which is selected from the group consisting of:14-oxa-14-(3,5-dichlorophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(4-nitro-3-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(3-nitro-2-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(3-nitro-4-methylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(2-fluoro-3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(3,4,5-trimethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(5,6,7,8-tetrahydronaphthalen-1-yl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(2-chloro-3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(3-chloro-4-flourophenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(3-triflouromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(3-triflouromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(4-chloro-3-ethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(4-methylindan-7-yl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(4-chloro-3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;14-oxa-14-(4-chloro-3,5-dimethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;and14-oxa-14-(4-fluoro-3-trifluoromethylphenyl)-5-(4-carboxythiazol-2-yl)-9-oxo-1,2,3,4,15,16,17,18,19,20-decanor-5-thia-8-azaprostane;or the pharmaceutically acceptable salt thereof or the cyclodextrinclathrate thereof.